Current Issue 2019: Volume 2, Issue 3

Post-translational Modifications (PTMs), from a Cancer Perspective: An Overview

B Sharan Sharma1,2, Vaishna Prabhakaran1, Akash P Desai1, Jaya Bajpai1, Ramtej J Verma2, Prabodha K Swain1*

1Life Sciences Research Division, Indrashil Institute of Science & Technology (IIST), Indrashil University (IU), Kadi, Mehsana – 382740, Gujarat, India

2Department of Human Genetics, Zoology & Biomedical Technology, University School of Sciences, Gujarat University, Navrangpura, Ahmedabad – 380009, Gujarat, India

Received: April 17, 2019
Published: May 8, 2019

*Corresponding author:

Dr. Prabodha K Swain

Life Sciences Research Division, Indrashil Institute of Science & Technology

Indrashil University (IU), Kadi, Mehsana - 382740, Gujarat, India

 

ABSTRACT

Studies on post-translational modifications (PTMs) have grabbed attention of the scientific community worldwide, its role in pathogenesis of cancer and prognostic biomarkers associated with cancers. However, unraveling the specific role of PTMs in carcinogenesis or in predictive biomarkers requires holistic understanding of the cancer types and associated mechanisms. Manifestation of cancer is complex and involves multiple steps including modifications at the levels of genes, associated proteins and signaling pathways. Biomarkers, as a prognostic marker, are critical in deciding efficacy of the clinical outcomes in malignancies. Growing evidence suggests that several biomarkers that are post-translationally modified play important role in human cancers. In the current review, few of such biomarkers and targets that are post-translationally modified and are associated with carcinogenesis are collated and analyzed to provide a bird’s eye view of their role in cancer types. Such analysis will help in understanding the pathogenesis and the precise role of biomarkers in designing better therapeutic interventions for different cancer types.

 

KEYWORDS: Cancer Markers; Oncoproteins; Kinase; Phosphorylation; Methylation

 

METHODS

The writing of this review involved a comprehensive search of original articles and reviews published on the subject of post translational modifications. Free search engine PubMed was used to conduct the online search. Sorting option ‘Best Match’ of PubMed was used to conduct the more relevant search. Various expressions were used to find relevant references for example, “post translational modifications in cancer”, “acetylation in cancer and post translational modifications”, “methylation in cancer and post translational modifications”, “biomarkers in cancer” etc. Some other expressions were used to conduct a more specific search to complement the findings in the articles retrieved with the more general search criteria for example, “checkpoint kinase 1 in cancer”, “candidate tumor suppressor BTG3” etc. Further, some articles were also found through reading of previous reviews on similar subjects including the ones by Karve and Cheema [1], and Han et al, [2]. Articles clearly related to the theme of this review and those that matched the search criteria were selected according to their year of publication (only articles published after 2000 were included in this review, except in specific situations) and relevance to the aims of this review.

 

INTRODUCTION: Clinically relevant post-translational modifications (PTMs)

‘Omic’ technologies (genomics, transcriptomics, proteomics and metabolomics) have evolved rapidly over the last decade. Evolution of these technologies has offered ample potential in the hunt for molecular markers of early stage cancers. However, these methods can be insufficient to investigate the dynamic nature of signaling processes that cells exhibit during their transformation to become tumor [3].

During the transformation of a cell from normal to neoplastic (tumorous) many important signaling events takes place which are controlled by the diverse realm of post-translational modifications (PTMs) [4]. PTMs are one of the critical regulatory mechanisms of cells affecting a number of biological functions. Various proteins are controlled by PTMs which are, in general, reversible. Since 2000, >54K articles on PTMs have been published as per the data obtained from PubMed. More than 450 unique protein modifications have been identified till date [2], including acetylation, methylation, phosphorylation, SUMOylation and ubiquitination, all of these PTM types can modify the activity of target proteins.

PTMs offer an abundance of potential candidates for biomarker detection hence PTMs related to these biomarkers should well be pursued for development of promising surrogate markers. Applications of many forms of PTMs have been identified in cancer medicine, however, for several other PTM types, applications are not yet readily apparent. It is worthwhile to explore different types of PTMs as they may prove valuable in near future to improve our understanding of carcinogenesis and fight against it. This review focuses on recent advancements in our understanding of various PTMs in the perspective of carcinogenesis. Some of the prominent proteins and associated PTMs relevant to carcinogenesis investigated by many laboratories are highlighted in Table 1.

Table 1: Post-translational modifications (PTMs) associated with proteins causative to oncogenesis

Protein

Post-translational Modification (PTM) Type

General Expression Pattern in Cancer

Reference

NF-kB

Acetylation

Overexpressed

[5]

LDH-A

Overexpressed

[6]

p53

Under-expressed

[7]

GP73

Glycosylation

Overexpressed

[8]

MUC1

Overexpressed

[9]

MUC16

Overexpressed

[10]

CD44

Overexpressed

[11]

GPCR

Methylation

Overexpressed

[12]

HMGB1

Overexpressed

[13]

RIOK1

Overexpressed

[14]

CHK1

Overexpressed

[15]

UBE2F

Neddylation

Overexpressed

[16]

HuR

Overexpressed

[17]

PTEN

Phosphorylation

Under-expressed

[18]

STAT-3

Overexpressed

[19]

Osteopontin

Overexpressed

[20]

EGFRs

Overexpressed

[21]

AKT

Overexpressed

[22]

p53

Under-expressed

[23]

DAPK1

Overexpressed

[24]

Rho

Prenylation

Overexpressed/Under-expressed

[25]

Ubc9

SUMOylation

Overexpressed

[26]

FOXK2

Under-expressed

[27]

HIC1

Under-expressed

[28]

CHK1

Ubiquitination

Overexpressed

[29]

p53

Under-expressed

[30]

Braf

Overexpressed

[31]

Ras

Overexpressed

[32]

 

 

Acetylation

Acetylation has emerged as a dynamic post translational modification that plays a key role in regulating nuclear transcription and metabolic homeostasis [33]. It mediates regulation of cellular processes, intermediary metabolism and metabolic enzymes via enzymatic activation or inhibition and further influence protein stability. Acetylation reactions are catalyzed by various N-terminal (NAT) and lysine acetyltransferases. Lysine acetylation, in particular, is enzymatically reversible and is tightly regulated by metabolism-dependent mechanisms.

Our understanding of protein acetylation has increased significantly in recent years by global proteomics analyses. Kim et al, [34] conducted the first proteomic survey for the acetylation modification and identified 388 acetylation sites in 195 proteins among the proteins derived from HeLA cells and mouse liver mitochondria. A comprehensive characterization of protein acetylation dynamics using mass spectrometry (MS) based proteomics revealed around 1,000 sites with significantly increasing acetylation trends [35].

Acetylation and deacetylation interplay is the key for many important cellular processes, malfunctioning in this machinery can result in severe conditions such as cancer, neurodegenerative diseases and cardiovascular disorders [36, 37]. Acetylation specific site mutations are enriched in cancer with decreased patient survival [38]. A recent study found 2106 acetylation-related single nucleotide variants (SNVs), 6405 ubiquitination-related SNVs, and 883 SNVs in shared sites of the two PTMs, covering cancer samples of various types, in this study, several known oncoproteins (TP53, AKT1 and IDH1) were shown to be modified for acetylation in cancer [38].

Histone deacetylases (HDACs) are involved in the deacetylation of not only histone proteins but non-histone proteins as well, regulating important functions. Studies have indicated that HDACs can regulate the expression of genes by direct interaction with transcription factors such as E2f, Stat3, p53 etc. [39]. Altered HDAC activity is linked to tumor development, identifying HDACs among one of the most promising biomarkers/targets in cancer research. Vorinostat, the first FDA-approved HDAC inhibitor, is used in the treatment of relapsed and refractory cutaneous T-cell lymphoma (CTCL) [40].

Acetylation has many important effects on oncoprotein p53, it increases p53 protein stability. In many cell types, inhibition of HDACs that remove acetyl groups from p53 (i.e., HDAC1 and SIRT1) causes increased p53 acetylation and p53-dependent activation of apoptosis and senescence [41]. Acetylation is an essential regulator of the anti-cancer functions of p53 [42]. In a study it was deduced that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity [7].

It has been shown that expression of NATs may both be increased and decreased in cancer versus non-cancer tissues and these acetyltransferase enzymes have been suggested to act as oncoproteins as well as tumor suppressors in human cancers [37]. Acetylation is an important modification of proteins with effects on the metabolome level and is an important research area to understand its physiological consequences.

 

Methylation

Methylation is a comparatively budding and promising area of research which has emerged as a prevalent post-translational modification. Methylation of arginine/lysine residues on non-histone proteins frequently mediates the transduction of cellular signals. With recent technological advancements the stage is now set to decode the ‘methylproteome’ to delineate its functions in health and disease [43].

Methylation of non-histone protein has an important regulatory role to play in a wide range of cellular processes [44] including transcriptional regulation, RNA metabolism and DNA damage repair. Various proteins involved in DNA repair (MRE11, p53, DNA polymerase b) have been shown to be controlled by arginine/lysine methylation [45].

With growing number of lysine methyltransferases (methylate non-histone proteins on lysine residue), a number of proteins like ERα, NF-κB, pCAF and other transcription factors have been identified that have implications in tumorigenesis and other metabolic disorders [1]. In addition to regulating gene expression, protein modification by methylation also contributes to the regulation of protein stability [46]. In a recent study, it was highlighted that BTG3 (B-cell translocation gene 3), a candidate tumor suppressor, promotes methylation of CHK1 (checkpoint kinase 1), a vital checkpoint kinase essential to normal cellular functions [15]. CHK1 has also been shown to be methylated in response to ultraviolet-induced DNA damage [47].

DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is an important epigenetic modification. Plentiful studies have examined expression of DNMTs in tumor tissues, especially expression of DNMT1 [48, 49]. PTMs play a crucial role in determining the correct functions of DNMT1. Altered role of DNMT1 results in aberrant methylation patterns which may initiate tumor formation. Presently, possibilities of DNMT1 as a new target for many tumors including breast cancer are being explored.

Arginine/lysine residues methylation is dynamic and reversible which can be removed by demethylation enzymes [50]. Identification of mechanisms involved in protein methylation/demethylation remains an interesting area of research to understand the regulatory roles of target proteins in cancer and other diseases.

 

Phosphorylation

Phosphorylation is one of the most prominent PTM of proteins and is an important cellular regulatory mechanism as through phosphorylation and dephosphorylation events many proteins, enzymes and receptors are regulated. Phosphorylation is a reversible mechanism and regulates numerous cellular processes such as protein synthesis, cell division, signal transduction, cell growth, development and aging which happen through protein kinases and phosphatases. Especially, the protein kinases are accountable for cellular transduction signaling and their overexpression or malfunction is found in several diseases, mostly tumors [51]. Therefore, targeting protein kinases using kinase inhibitors can be valuable for the treatment of cancer. The most common amino acid residues modified for phosphorylation are serine (Ser or S), threonine (Thr or T), and tyrosine (Tyr or Y), they also play indicative role in progression of cancer [18, 52].

A number of cellular signalling pathways including tyrosine kinase, MAP kinase, cadherin–catenin complex and others are major players of the cell cycle, and deregulation in their phosphorylation-dephosphorylation cascade has been shown to be manifested in the form of various types of cancers [53]. Phosphorylation of Akt/protein kinase B (PKB), a serine/threonine kinase which mediates a variety of biological responses, has a prognostic and/or predictive role of in several cancers including breast, prostate and non-small cell lung cancer [54]. Dysregulated tyrosine kinase activity is reported in different types of cancers for example amplification of Her2/neu was observed in tumor cells of breast cancer [55]. MAPK cascade (SOS-Ras-Raf- MAP kinase pathway), involved in the regulation of normal cell proliferation, differentiation and apoptosis, has an important role in cancer growth and progression [56].

Additionally, the importance of Raf and MEK in cancer progression and in promoting cancer growth has been well established [57]. Tumor suppressor p53 phosphorylation sites, Ser315 and Ser392 in the C-terminal regulatory domain, are associated with elevated p53-dependent transcription [58]. During DNA damage, expression of proapoptotic protein Bax, members of the Bcl-2 (B?Cell Lymphoma 2) family of proteins, is upregulated by the protein p53. Such apoptotic pathways are the focus of cancer researchers to develop new drugs.

To sustain the functional integrity of the cadherin–catenin complex phosphorylation is an important process. Dysregulation of this process has been found to be strongly associated with cell-adhesion defects in carcinomas including prostate cancer progression [53,59]. Studies have revealed that transforming growth factor β (TGF β) prevents the phosphorylation of retinoblastoma protein (pRb) which leads to its inactivation [60]. This signaling is altered in many human cancers [61], in some of which impassiveness of cyclin-CDK4 complex to the inhibitory signals of p15INK4B leads to inactivation of pRb by hyperphosphorylation [62].

Phosphorylation pathways are crucial regulators of normal cellular functioning and these pathways are needed to be considered for more rational treatment of cancer.

 

SUMOylation

SUMOylation is a widely occurring reversible PTM which has attracted increasing attention as it is involved in a number of biological processes for the maintenance of genomic integrity. Small ubiquitin-like modifier (SUMO) is structure wise similar to that of ubiquitin and is covalently attached to lysine residues of specific target proteins [63], SUMO1, SUMO2/3 and SUMO4 are the identified SUMO isoforms. SUMO pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of DNA damage repair, gene expression, cellular signaling, cell cycle progression and apoptosis. Irregular SUMOylation can lead to the progression of a number of diseases, including cancer. The vital role of SUMOylation in tumorigenesis has gradually emerged [64].

Studies have shown that SUMOylation plays an important role in cancer [64] and many oncogenes and tumor suppressors are functionally regulated via SUMOylation [65]. BRCA1, a tumor suppressor gene in humans associated with breast and ovarian cancer is modified by SUMO in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9 [66].

SUMOylation has varied effects on transcriptional activity of androgen receptor (AR) which has an established role in prostate carcinogenesis [67]. SUMO-resistant DNA endonuclease, Mus81 mutants involved in homologous recombination repair, display compromised DNA damage responses associated to tumorigenesis [68]. An important SUMO-conjugating enzyme in the SUMOylation pathway, Ube2I, SUMO-inducer ARF and the SUMO-ligase PIAS1 were seen greater than normal levels in multiple myeloma patients [69].

Tumor suppressor p53 promotes cellular senescence as well as apoptosis. SUMO-1 conjugation with p53 has been shown to result in p53 stabilization and activation, causing the induction of senescence [70]. DNA damage signals or oncogenic mutations induce SUMO disorders that ultimately lead to cell senescence, effects of this on tumor or tumor microenvironment is the current focus of research.

SUMO modification, as an important PTM, is a key to regulating cell activities. It has been accepted and confirmed by research that SUMO modification plays a vital role in the pathological processes. SUMO modification is linked with tumorigenesis and targeting SUMO pathways could be exploited in anticancer therapies.

 

Ubiquitination

Ubiquitination, as a multistep, conserved and highly dynamic process, functions to degrade and recycle proteins. It is involved in additional cellular processes such as activation of NFkB inflammatory response and DNA damage repair [71]. Ubiquitination also affects the result of many lethal diseases like cancer [72]. Three main classes of ubiquitination enzymes are activating enzymes (E1), conjugating enzymes (E2), and ligases (E3). Unregulated expression of these enzymes, including DUBs (deubiquitinating enzymes) and other complexes (SCF complex) involved in ubiquitination mechanism, contributes to the signaling of various oncogenes leading to cancer progression and metastasis.

Ubiquitination displays parallel properties with phosphorylation but distinguishes itself in important ways [73]. As a marker, phosphorylation often triggers subsequent ubiquitination, in particular where ubiquitination leads to degradation [74], and in other cases ubiquitination provide a switching mechanism that can turn on/off the kinase activity of certain proteins [75]. Hence, understanding the crosstalk between these important PTMs is crucial to explore how they regulate signal transduction.

Various studies have shown that E2 ubiquitin conjugating enzymes (for example UBE2N and UBE2C) are associated with aberrant oncogenic signaling of numerous molecules including inflammatory NFkB and TGFb, receptor tyrosine kinases and others [76,77,78]. Like E2 ubiquitin conjugating enzymes, altered expression of E3 ubiquitin ligases also leads to aberrant oncogenic signaling [71]. For example, enhanced expression of STIP1 Homology and U-Box Containing Protein 1 (STUB1), an E3 ligase, is found to be associated with pancreatic, prostate and other cancer types [79]. DUBs are also important players of cellular processes such as DNA repair and cell cycle progression. Several studies have shown that altered than normal role of DUBs is involved with cancer progression [80,81,82]. It is clear that various enzymes involved in ubiquitination are linked with cancer progression hence there is need to develop therapeutic agents targeting these enzymes to counter the oncogenic pathways.

 

PTMs based Cancer Markers

The understanding of mechanisms of PTMs has contributed to the identification of new biomarkers which are of relevant to clinical practice, enabling researchers to use targeted therapeutic approaches in the treatment of cancer. Specific inhibitors are being developed and testing of such inhibitors against target protein may prove to be effective in targeting certain types of cancer. The significance of crosstalk between different types of PTMs has been well recognized and targeting one or the other modification has been the focus area of cancer research.

Discovery of novel anticancer drugs is critical for treating patients. This search of anticancer compounds is based on the genes, associated proteins and pathways which have been implicated in tumorigenesis. For example, in a recent study, a comparative global methylation profiling resulted in identification of 7 hyper-methylated (e.g., FBN1, LPP, and SOD3) and 61 hypo-methylated (e.g., HBE1, SNRPF, TPD52) markers for gallbladder cancer (GBC) [83]. Oncology drugs approved lately, target distinct cancer biomarkers or pathways in tumor cells. Table 2 lists some examples of the important cancer biomarkers, all of them are known to be post-translationally modified, and effectively targeted for the development of drugs. We have briefly discussed below some PTM based biomarkers associated with carcinogenesis.

Table 2: Validated targets approved as cancer therapy and prognostic markers

Cancer Biomarker

Indication

Druga (Company)

EGFR

 Lung Cancer

Iressa/Gefitinib (AstraZeneca)

KRAS

Colorectal Cancer

Erbitux/Cetuximab (Eli Lilly)

HER2

Breast Cancer

Herceptin/Trastuzumab (Genentech)

BRAF

Melanoma

Mekinist/Trametinib (Novartis)

BCL-2

Leukemia

Venclexta/Venetoclax (AbbVie/Genentech)

CD117 (KIT)

Gastrointestinal Tumors

Gleevec/Imatinib Mesylate (Novartis)

ALK

Non-Small Cell Lung Cancer

Zykadia/Ceritinib (Novartis)

PI3K Delta

Lymphoma

Zydelig/Idelalisib (Gilead)

DNMT1

Leukemia

Natdecita/Decitabine (Natco)

SMO

Basal Cell Carcinoma

Erivedge/Vismodegib (Genentech)

 

aMost of these drugs are recommended with companion diagnostics (CDx)

 

PTMs directly modulate the cellular signaling and trafficking of an important cell component, epidermal growth factor receptor (EGFR). EGFR is an important cancer biomarker owing to the molecular events associated with cancer. EGFR protein-protein interactions and PTMs are responsible for its signaling and trafficking which have been extensively studied [84]. Upon X-rays and chemotherapy treatments, EGFR becomes phosphorylated and this event is accompanied by receptor internalization provoking p38 or Src-dependent, and clathrin- and AP-2 adaptor-dependent endocytic trafficking [85,86,87]. It has been shown that abolishing p38-dependent EGFR internalization diminishes the efficacy of chemotherapy-induced cell death therefore promoting the cytotoxic effect of chemotherapy drugs such as Cisplatin [87]. Drugs, for example Gefitinib (Iressa) and Erlotinib (Tarceva), has been approved with either a companion or complementary diagnostic to target activating EGFR mutation (EGFR M+) in non-small cell lung cancer (NSCLC). Mutations involving the PTM sites of EGFR impair EGFR trafficking. EGFR sites, tyr1068 and tyr1173, are among the two most relevant phosphorylation sites of EGFR, and phosphorylation at tyr1068 has been identified as a powerful biomarker associated with strong Erlotinib sensitivity in lung cancer stem cells (LCSCs) [21]. In contrast, a recent study provided additional mechanistic aspects of EGFR regulation by showing that mutations preventing EGFR phosphorylation at tyr998 or in the ser1039 region abolished or greatly reduced EGFR interactions with Adaptin subunits AP-2 and AP-1, and resulted in impaired receptor trafficking [88]. Studying the biological effects of such events are is important to determine the efficacy of EGFR-targeting drugs.

Human epidermal growth factor receptor-2 (HER2) is another important cancer biomarker which is overexpressed in large number of breast cancers. HER2 is activated by phosphorylation at specific tyrosine residues. Strong expression of activated HER2 is associated with poor prognosis in HER2 positive breast cancer patients. Experiments on primary breast tumors showed that strong expression of HER2 phosphorylated at tyrosine 1221/1222 is associated with poor prognosis in HER2 positive breast cancer patients [89].

To treat HER2 positive breast cancer patients, drug Trastuzumab (Herceptin) is used which inhibits HER2 signaling and its subsequent activation. Inception of companion diagnostics was with Herceptin. Herceptin mechanism involves inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment [90]. However, Herceptin resistance has been noted in some patients possibly due to failure to abolish HER2 phosphorylation, therefore, alternate treatment opportunities are also being explored to overcome acquired resistance in breast cancers. Studies have confirmed that Herceptin although down-regulated HER2 receptors in HER2-positive breast cell lines but failed to decrease HER2 phosphorylation as this phosphorylation was maintained and increased by the ligand-induced activation of EGFR, HER3, and HER4 receptors, resulting in their dimerization with HER2, by a protein kinase B (PKB) negative feedback loop [91]. Similar feedback loops might also be involved in the acquired resistance to Herceptin, an area of further research.

Physical blockade of the HER2 receptor is a further proposed mechanism for Herceptin resistance, for example, the mucin molecule, MUC4, with its extended carbohydrate structure seems to function as a barrier for biomolecular interactions in the extracellular environment [92,93]. A recent study highlighted the importance of cellular glycosylation on the binding of the drug Herceptin to the surface of cancer cells, the responsiveness of cancer cells to a chemotherapeutic agent, and potential of glycosylation inhibitors as future combination treatments for breast cancer [94]. This study showed the importance of the glycocaylx in the accessibility of the HER2 epitope to Herceptin [94], influencing many aspects of cancer cell biology and drug responsiveness since glycosylation affects many proteins.

Abnormal protein glycosylation is a well-known event in oncogenesis which modulates the response of cancer cells to chemotherapeutic and biological treatments. Glycoproteins and/or altered tumor-associated carbohydrate antigens are targeted and recognized by many currently employed antibodies that recognize commonly occurring alterations in neoplastic cell antigens. Several of these glycobiomarkers including cancer antigens, mucins, integrins, HER2, and other tumor-associated glycoproteins are currently in use for management of human cancers [95]. With modern studies, it is clear that glycan-markers give us the opportunity to use them as a tag for recognition and possible targeting of tumors. Glycobiomarkers, for example, mucin-type O-glycans Tn and its sialylated version STn carbohydrate antigens, expressed highly by many types of tumors, may serve not only as a prognostic marker but also as a therapeutic target [96]. Not only as a biomarker but also as a contributor to the cancer development, protein glycosylation is an important phenomenon. It is therefore imperative to explore tumor-associated glycosylation as it provides novel diagnostic and therapeutic targets.

Estrogen receptor α (ERα) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. Redox- and phosphorylation-based PTMs are important and common modifications of ERα along with several other reported ERα PTMs, many of these modifications modulate receptors activity in breast tumors [97]. Important phosphorylation sites have been identified in endogenous ERα derived from the human breast cancer cell lines [97]. Phosphorylation of ERα induced by a growth factor pathway might be one mechanism of enhanced activation of the estrogen signal [98], for example, sites targeted by kinases such as MAPK, Akt, and c-Src [99]. ERα degradation by ubiquitin-ligase activity is another important factor controlling ERα signaling. It has been suggested that E3 ubiquitin ligase ring finger protein 31 (RNF31) and p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) might be useful therapeutic targets in ERα-positive breast cancer. Both RNF31 and PAK4 act as modulator of ERα protein level by means of ubiquitination and phosphorylation mechanisms, respectively [100,101]. Alterations contributing to increased activity, and diminished degradation of ERα protein are likely to contribute to the pathogenesis of ERα-positive breast tumors.

Ubiquitously expressed E3 ligase protein cereblon (CRBN) has been emerged as a therapeutically important cancer biomarker in hematological malignancies. Drugs like Thalidomide and its second generation derivatives, Lenalidomide and Pomalidomide, have been approved to target CRBN by preventing its auto-ubiquitination [102].

A number of proteins have been identified to be associated with tumorigenesis directly or indirectly. Exploration of the effects of various PTMs on these proteins and further dissection of their mechanisms of actions will help in identification of novel cancer biomarkers and will also pave the way for newer therapeutic opportunities to target cancer. Nevertheless, noteworthy advancements have been made in the search for biomarkers related to PTMs and cancer. However, targeting of these biomarkers and associated pathways remains challenging.

 

Conclusion and Future Perspectives

With new PTMs being unraveled, more and more proteins are being discovered to be involved in the pathogenesis of multiple diseases including cancer. The broad spectrum of PTMs imparts both metabolic and non-metabolic benefits to cancer cells. It is crucial to understand the key mechanisms associated with PTMs and their pathways, and also the crosstalk between various PTMs which will eventually expand our understanding to refine the clinical targeting of cancer biomarkers linked with PTMs and to contribute towards drug development for the treatment of cancers. Systematic identification along with functional and mechanistic characterization of PTMs of target proteins would aid in the development of innovative strategies for drug discovery and cancer therapy.

Better understanding of cancer dependency on PTMs and to anticipate the associated molecules and pathways is one of the major challenges in the future drug discovery. Overall good clinical response with current and new drugs under investigations is seen, however, with the emerging drugs, their resistance is also growing. This emerging resistance is another challenge scientists are weathering. Understanding resistance mechanisms will lead to deeper understanding of carcinogenesis and will also pave the way to discover new generation drugs with profound selectivity to overcome resistance. With new drugs, a large number of clinical trials will also be warranted to validate the efficacy of drugs.

Factual state of cancer progression may not be completely reflected by simply observing the changes in gene expression levels therefore it is important to study PTMs to find out the differences between normal and cancer tissues. Further study and evaluation of various functional modifications of proteins and their role in biological pathways will be instrumental in broadening the avenue of translational medicine for deadly diseases like cancer.

 

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Copyright: Sharma BS, et al. ©2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution,
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Citation: Sharma BS (2019). Post-Translational Modifications (PTMs), from a Cancer Perspective: An Overview. Oncogen 2(3): 12.

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