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Review
. 2021 Mar 27;22(7):3458.
doi: 10.3390/ijms22073458.

Gene Transactivation and Transrepression in MYC-Driven Cancers

Marika Scafuro  1 , Lucia Capasso  1 , Vincenzo Carafa  1 , Lucia Altucci  1 , Angela Nebbioso  1
Affiliations
Review

Gene Transactivation and Transrepression in MYC-Driven Cancers

Marika Scafuro et al. Int J Mol Sci. .

Abstract

MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.

Keywords: MYC; MYC deregulation; MYC-driven cancers; epigenetic modulation; therapeutic target; therapy resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
MYC regulation of distinct cellular functions. Many biological processes are regulated by MYC. Elevated MYC levels can result in deregulation of a subset of genes involved in cancer development.
Figure 2
Figure 2
Domain architecture of MYC protein and its interacting partner MAX, showing MYC protein residues and their different functional characteristics. N-terminal region interacts with several partners and C-terminal region binds MAX via b-HLH-LZ motif. MYC:MAX heterodimer binds canonical and non-canonical E-box DNA sequences of target genes.
Figure 3
Figure 3
MYC-mediated transactivation and transrepression of target genes. Transcriptional activation of target genes (A). MYC:MAX heterodimer binds E-box sequences and transactivates canonical target genes through recruitment of chromatin modifying co-factors. TIP60 and GCN5 via transformation/transcription domain-associated protein (TRRAP) and p300/CBP, respectively, increase acetylation of histone H3 and H4, inducing an open chromatin conformation allowing RNA polymerase II machinery to bind the core promoter. Histone demethylases (KDMs) regulate the methylation of histone H3 by removing repressive chromatin marks, thereby contributing to gene activation. PIM1 phosphorylates histone H3 and MYC increasing its stability. Aurora A protein kinase (AURKA) phosphorylates and stabilizes MYC. WDR5 is crucial for recruitment of MYC at chromatin regions. Transcriptional repression of target genes (B). MYC:MAX/MIZ1-mediated transrepression of non-canonical target genes involving recruitment of chromatin co-repressors. MYC:MAX/MIZ-1 complexes recruit DNMT3A to non-canonical targets, thereby increasing tri-methylation of histone H3, promoting tumor cell proliferation rather than differentiation and senescence. HDAC1 and HDAC3 contribute to histone deacetylation and thus gene silencing. EZH2 is a member of PRC2 that catalyzes tri-methylation of histone H3 to enhance gene silencing. Bromodomain PHD finger transcription factor (BPTF) is necessary for MYC transcriptional activity.
Figure 4
Figure 4
MYC-targeted therapies. Current therapies targeting MYC using direct and indirect inhibition strategies leading to tumor suppression.
See this image and copyright information in PMC

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