Regulation and Function of the MYC Oncogene

Abstract

One of the most acclaimed features of the MYC oncogene family (MYC, MYCL1 and MYCN) is their prolific deregulation in cancer, which is often associated with poor prognosis and refractory disease. Multiple mechanisms can deregulate their expression in cancer, including chromosomal translocation, enhanced messenger ribonucleic acid (mRNA) and protein stability, gene amplification or enhancer hijacking. This MYC family of nuclear transcription factors regulates the expression of a multitude of target genes to control many critically important fundamental biological processes, including cellular proliferation, metabolism, apoptosis and embryonic development. MYC proteins are highly regulated, and many factors have been reported to control stability and activity via post‐translational modifications (PTMs). Decades of research into this potent oncogene family have revealed that while directly inhibiting MYC proteins in cancer remains challenging, there are multiple strategies to indirectly inhibit MYC in cancer. Developing such inhibitors to target MYC would have profound impact on patient care and outcome.

Key Concepts

  • The MYC family of oncogenes, composed of MYC, MYCN and MYCL1, encode nuclear basic helix‐loop‐helix transcription factors.
  • MYC family proteins contain highly conserved regions termed MYC boxes.
  • MYC regulates many transcriptional targets and can have wide‐reaching effects on the epigenome and total cellular RNA content.
  • MYC is essential for cellular proliferation and is a potent oncogene when it is deregulated in cancer.
  • Deregulated, often elevated, MYC levels have been shown to drive tumourigenesis in many in vivo models.
  • MYC activity and stability is regulated by post‐translational modifications, including phosphorylation, ubiquitylation, SUMOylation and acetylation.

Keywords: MYC; oncogene; cancer; transcription factor; post‐translational modifications; tumourigenesis

Figure 1. Schematic of MYC family proteins. Abbreviations: B, basic region; HLHLZ, helix‐loop‐helix leucine zipper region; MB, MYC boxes and TAD, transcriptional activation domain. T58 and S62 phosphorylation sites are highlighted in yellow, and T58 is notably mutated in viral MC29 MYC.
Figure 2. Potential therapeutic opportunities to target deregulated MYC in tumours. (a) The small molecule inhibitor JQ1 has been demonstrated to inhibit MYC transcription. (b) Inhibitors of MYC protein stability, such as those targeted to USP28, have the potential to decrease MYC levels. Ub, ubiquitin. (c) Inhibitors of cofactors essential for MYC transcriptional activity have the potential to be direct inhibitors of MYC activity. (d) Omomyc has provided a proof of concept that inhibitors of MYC–MAX association have potential for therapeutic utility. (e) Synthetic lethal screens have identified a number of vulnerabilities in cell lines with deregulated MYC and provide an indirect method to target MYC‐deregulated tumours.
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Further Reading

Dang CV (2012) Myc on the path to cancer. Cell 149 (1): 22–35.

Eilers M and Eisenman RN (2008) Myc's broad reach. Genes and Development 22 (20): 2755–2766.

Kalkat M, De Melo J, Hickman KA, et al. (2017) MYC deregulation in primary human cancer. Genes 8 (6). DOI: 10.3390/genes8060151.

Luscher B and Vervoorts J (2012) Regulation of gene transcription by the oncoprotein Myc. Gene 494 (2): 145–160.

Wasylishen AR and Penn LZ (2010) Myc: the beauty and the beast. Genes & Cancer 1 (6): 532–541.

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Kalkat, Manpreet, Resetca, Diana, and Penn, Linda Z(Jun 2018) Regulation and Function of the MYC Oncogene. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024149.pub2]