Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance
Graphical abstract
Introduction
Cancer cells tend to possess both genetic and epigenetic alterations that give malignant phenotypes. These alterations are integrated into all the stages of cancer development and the chemoresistant phenotype [1]. As most genetic alterations are considered irreversible, importance is being given to fix the cancer-promoting epigenetic alterations because of its dynamic and reversible nature. Epigenetic changes do not affect the sequence of the DNA; instead, regulate the changes of various biological processes or cellular activities by imposing chromatin modifications, nucleosome remodeling, histone modifications, RNA, and protein modifications [2,3]. There are multiple proteins responsible for epigenetic modifications and classified them according to the role they play. The machinery associated with epigenetic changes has garnered much attention in recent years and is being investigated [4]. A wide variety of epigenetic markers are recognized, and the science of epigenetics is rapidly growing in different fields of biology [2,4,5].
Epigenome comprises the multitude of chemical modifications that have been added to the entirety of the genome and regulate its expression. Epigenome includes reversible modifications of DNA and histone proteins such as hypermethylation, hypomethylation, acetylation, and deacetylation, which can cause chromatin remodeling and altered transcriptional and translational activity of the genes [2,4,5]. While epigenetic changes are essential for normal physiology and development, they can also be responsible for different diseases such as cardiovascular disease, cancer, etc. Epigenetic regulations and dysregulations play a significant role in cancer development, progression, and chemoresistance. Extensive research on various aspects of epigenetic modifications in cancer could help in probing various therapeutic targets and for better management of different cancer [1,6].
Epigenetic regulators and modifications play a pivotal role in cancer cell reprogramming. Cancer cell reprogramming redirects the cancer cells to generate stem cell-like properties. The cellular reprogramming process gives insight into the multiple levels of cellular heterogeneity in the cancer microenvironment [7]. Cancer cells can quickly switch their phenotypic states, which is achieved by various epigenetic modifications that result in the inhibition of cellular differentiation and favor acquired pluripotency [8]. Epigenetic modifications of transcription factors such as c-MYC play a crucial role in regulating various aspects of cancer cell reprogramming, progression, and chemoresistance (Fig. 1). Further, direct modification of their mRNA transcripts can play a role in this process [9]. Epigenetic modification of tumor suppressors can also deregulate the expression of c-MYC and contribute to the various level of cancer pathogenesis [10].
c-MYC plays an essential role in balancing the fine line between normal cells and transformed cells. Epigenetic modifications of c-MYC influence the multiple essential functions of the cells. Epigenetically modified c-MYC protein has higher stability, contributing to decreased cell death and increased cell proliferation in cancer cells and cancer stem cells (CSCs) [11]. Foley et al. [12] reported that various epigenetic modifications of the c-MYC promoters play an essential role in imparting chemoresistance in cancerous cells. Further, c-MYC is epigenetically regulated and alter various downstream molecules that play an essential role in cancer. For example, c-MYC induces E6 oncoprotein and contributes to the transactivation of human telomerase reverse transcriptase (hTERT) promoter through histone modifications in head and neck carcinoma [13]. Meeran et al. [14] observed that histone acetyltransferases (HAT) co-activator complexes facilitate the open chromatin structure through histone acetylation. Open chromatin structure helps occupy c-MYC on the hTERT promoter region and regulates its transcription [14]). Besides, SIRT1 deacetylates c-MYC in various cancers. Deacetylated c-MYC forms a complex with Max and regulates the hTERT promoter [15,16].
Chemotherapeutic drugs generally interact with various cellular targets and induce cell death. However, over time the cancer cell tends to stop responding to the therapy and acquire chemoresistance. Reports are accumulating, which suggests that epigenetic modifications play a crucial role in conferring chemoresistance. Depending upon the type of epigenetic modification, epigenetic gene silencing may chemosensitize the therapy-resistant cells, or it may sometimes confer chemoresistance [17]. Epigenetic aberrations of crucial proteins are also linked with chemoresistance in several cancer types and can serve as a putative biomarker for epigenetic therapies [18,19]. DNA demethylating agents, histone deacetylase (HDAC) inhibitors, and HAT are reported to sensitize the chemoresistant cells for therapies [20,21]. Epidrugs or epigenetic drugs are a set of chemical compounds that can epigenetically alter the targeted proteins and reactivate or suppress their functions [9]. Different kinds of epidrugs are also being researched, which can help in suppressing the role of oncogenes by epigenetically modifying them [9]. In this review, we have summarized the role of epigenetic modifications of c-MYC and its role in cancer development, reprogramming, and chemoresistance. We also address how epigenetic modifications of c-MYC might be exploited as therapeutic targets alone or, along with various other treatments in countering the cellular changes in the transformed cells.
Section snippets
Epigenetic regulations in Cancer
Epigenome warrants the functional specialty to different cells of the body that otherwise share the same genome. Aberrations in the epigenome are often implicated in the onset of different diseases, including cancer. Several investigative studies have highlighted a connection between cancer and the underlying epigenetic network [2]. Whole-genome sequencing has provided a catalog of various types of epigenetic mutations through somatic mutations in a vast array of cancer [22]. Further,
Epigenetic regulation of c-MYC in Cancer cell reprogramming, progression, and chemoresistance
c-MYC is one of the most frequently discussed transcription factors and plays a significant role in maintaining the exquisite balance between healthy and cancerous cells. In more than 50 % of human cancer, c-MYC is deregulated and most often affiliated with increased tumor aggression, confers chemoresistance, and reduced patient survival rate [37,38]. In various cancers, genetic alteration in c-MYC can lead to its derailment from normal regulatory constraints and desensitization from normal
Epigenetic regulation of c-MYC and Cancer cell reprogramming
Reprogramming of cancer cells results in the genesis of stem cell-like properties. It is also associated with chemoresistance and implicated in poor outcomes [7,8]. c-MYC is an essential regulator of reprogramming in various cancer cells and has the role of the enhancer, which amplifies the gene expression necessary for pluripotency [55]. Yue et al. [56] argued that the ectopic expression of c-MYC, along with other stem cell factors, could induce reprogramming of retinoblastoma cells into CSCs.
Epigenetic regulation of c-MYC and chemoresistance
ATP-binding cassettes (ABC) are a family of transporter proteins present on the plasma membrane that helps in the movement of a substance across the plasma membrane. ABC transporters can impart chemoresistance in cancer cells by effluxing the drug outside of the cells, rendering drugs useless in their function [17]. c-MYC dysregulates ABC transporter genes and is accountable for the multidrug resistance and decreased efficacy of therapies [19]. Hypermethylation of c-MYC is also associated with
Regulation of c-MYC by non-coding RNA
Studies based on the genome-wide transcriptome of the mammalian genome have revealed that a large portion of the genome is transcribed into RNA. The majority of the genome that gets transcribed into the RNA, less than 2% has the capability to translate as protein [63]. The untranslated RNA is designated as non-coding RNA (ncRNA), further classified into short ncRNA and long ncRNA (lncRNA). Short ncRNAs comprise less than 200 nucleotides, while lncRNA has sequences longer than 200 nucleotides [64
Targeting the regulatory network of epigenetically modified c-MYC
Current treatment strategies present limited efficacy in recurrent and chemoresistant cancers [63,82]. A number of studies have revealed that c-MYC are the central players in cancer recurrence and chemoresistance. Moreover, evidence has suggested that aside from genetic regulation of c-MYC on the various cancers, their epigenetic modifications also play a crucial role in cancer development, reprogramming, and chemoresistance. Most epigenetic modifications are reversible, and different
Conclusion and future perspective
Both basic and clinical oncologists widely accept epigenetic modifications of important factors in various cancers. Alterations of the epigenome in many of the cancers haves opened up the scope of novel therapeutic approaches. In this context, the central position of c-MYC in multiple cancers makes them very promising therapeutic targets. Direct inhibition of these molecules remains a challenge and sometimes impossible as they are essential to stem cell factors. Nonetheless, the discovery of
Funding source
All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated.
Author's contribution
Collection of literature and writing the manuscript: H. Fatma, S.K. Maurya, and H.R. Siddique.
Concept and Supervision: H.R. Siddique.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
The authors are thankful to the Aligarh Muslim University, India, for providing necessary facilities. HF and SKM express their sincere gratitude for fellowships to UGC and DST, India, respectively. HRS is thankful to the UGC [Grant no. F.30-377/2017(BSR)] and DST-SERB (Grant no. EMR/20l7/001758), New Delhi, India, for providing financial help. We also apologize to eminent researchers working in this field whose work could not be cited in the review due to limitations of space.
References (101)
- et al.
Epigenetic mechanisms as a new approach in cancer treatment: an updated review
Genes Dis.
(2018) - et al.
Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity
Trends Cancer
(2017) - et al.
An epigenetic pathway regulates sensitivity of breast cancer cells to HER2 inhibition via FOXO/c-Myc axis
Cancer Cell
(2015) - et al.
DNA methylation, histone acetylation and methylation of epigenetic modifications as a therapeutic approach for cancers
Cancer Lett.
(2016) - et al.
COMPASS ascending: emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer
Cancer Lett.
(2019) - et al.
Geometric regulation of histone state directs melanoma reprogramming
Commun. Biol.
(2020) - et al.
Epigenetic approaches to cancer therapy
Epigenetics in Human Disease
(2018) - et al.
Targeting oncogenic Myc as a strategy for cancer treatment
Signal Transduct. Target. Ther.
(2018) - et al.
Role of long non-coding RNAs and MYC interaction in cancer metastasis: a possible target for therapeutic intervention
Toxicol. Appl. Pharmacol.
(2020) - et al.
Transcriptional dysregulation of MYC reveals common enhancer-docking mechanism
Cell Rep.
(2018)
HCV core protein promotes hepatocyte proliferation and chemoresistance by inhibiting NR4A1
Biochem. Biophys. Res. Comm.
Reprogramming of retinoblastoma cancer cells into cancer stem cells
Biochem. Biophys. Res. Commun.
The essentiality of non-coding RNAs in cell reprogramming
Noncoding RNA Res.
Non-coding RNAs in cancer therapy resistance and targeted drug development
J. Hematol. Oncol.
MiR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3
Biochem. Biophys. Res. Commun.
Protein arginine methyltransferase 5 represses tumor suppressor miRNAs that down-regulate CYCLIN D1 and c-MYC expression in aggressive B-cell lymphoma
J. Biol. Chem.
EGFR/c-myc axis regulates TGFβ/Hippo/Notch pathway via epigenetic silencing miR-524 in gliomas
Cancer Lett.
Trials with ‘epigenetic’drugs: an update
Mol. Oncol.
Epigenetic modifications of histones in cancer
Genome Biol.
Epigenetic enzyme mutations: role in tumorigenesis and molecular inhibitors
Fron Oncol
Targeting epigenetics in cancer
Annu. Rev. Pharmacol. Toxicol.
Cucurbitacin B induces hypermethylation of oncogenes in breast cancer cells
Planta Med.
Codependency of metabolism and epigenetics drives cancer progression: a review
Acta Histochem. Cytochem.
Cancer cell reprogramming: a promising therapy converting malignancy to benignity
Cancer Comm
Epidrugs: targeting epigenetic marks in cancer treatment
Epigenetics
Epigenetics, miRNAs, and human cancer: a new chapter in human gene regulation
Mamm. Genome
BRD4 promotes gastric cancer progression through the transcriptional and epigenetic regulation of c‐MYC
J. Cell. Biochem.
Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling
J. Transl. Med.
Direct HPV E6/Myc interactions induce histone modifications, Pol II phosphorylation, and hTERT promoter activation
Oncotarget
Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines
PLoS One
Dual roles of c-Myc in the regulation of hTERT gene
Nucleic Acids Res.
Regulation of the telomerase reverse transcriptase subunit through epigenetic mechanisms
Front. Genet.
Current opinions on chem oresistance: an overview
Bioinformation
Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation
Sci Rep
Suberoylanilide hydroxamic acid (SAHA) reverses chemoresistance in head and neck cancer cells by targeting cancer stem cells via the downregulation of nanog
Genes Cancer
The DNA methylation landscape of advanced prostate cancer
Nat. Genet.
DNA hypermethylation encroachment at CpG island borders in cancer is predisposed by H3K4 monomethylation patterns
Cancer Cell
Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex
Biochem. J.
Histone deacetylase inhibitor entinostat inhibits tumor-initiating cells in triple-negative breast cancer cells
Mol. Cancer Ther.
Hypomethylation of the c-myc promoter region induced by phenobarbital in rat liver
Roczniki Państwowego Zakładu Higieny
Methods for analysis of specific DNA methylation status
Methods
Methylation-based therapies for colorectal cancer
Cells
DAXX suppresses tumor-initiating cells in estrogen receptor–Positive breast cancer Following endocrine therapy
Cancer Res.
Multifaceted role of PRDM proteins in human cancer. PRDM Proteins in Human Cancer
Int. J. Mol. Sci.
Symphony of epigenetic and metabolism regulation—interaction between the histone methyltransferase EZH2 and metabolism of tumor
Clin. Epigenetics
Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential
Biomarker Res.
METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification
Cell Stem Cell
DNA methylation and cancer
J. Clin. Oncol.
lncRNA PVT1 promotes hepatitis B virus-positive liver cancer progression by disturbing histone methylation on the c-Myc promoter
Oncol. Rep.
MYC deregulation in gastric cancer and its clinicopathological implications
PloS one
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