Regulation and Function of the MYC Oncogene

Abstract

The MYC oncogene has been the subject of intense study for more than 30 years, due to its important role in tumourigenesis. MYC is a nuclear transcription factor that can regulate the expression of a multitude of target genes, and its expression in tumours is often associated with poor prognosis. Although decades of research have provided insights into its molecular function as a transcription factor, the mechanisms by which MYC can induce cellular transformation have remained elusive. In addition to the regulation of genes important for cell cycle progression, metabolism, apoptosis and angiogenesis, MYC has wide‐reaching effects, including the alteration of cellular epigenetics and total ribonucleic acid (RNA) content. Recent reports have suggested that post‐translational modification (PTM) of MYC is important for regulating the activity and functions of this potent oncogene; however, surprisingly, little research has been conducted in this area. Herein, the authors summarise recent findings regarding the molecular and biological functions of MYC and their relationship to the PTMs of MYC.

Key Concepts:

  • The MYC oncogene encodes a nuclear basic helix‐loop‐helix transcription factor.

  • MYC regulates a large number of transcriptional targets and can have wide‐reaching effects on proliferation, 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 initiate tumourigenesis in many in vivo models.

  • MYC activity and stability is regulated by post‐translational modifications, including phosphorylation, ubiquitylation and acetylation.

Keywords: MYC; oncogene; cancer; post‐translational modification; transcription; 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. (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.

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

Meyer N and Penn LZ (2008) Reflecting on 25 years with Myc. Nature Reviews Cancer 8(12): 976–990.

Wasylishen AR and Penn LZ (2010) Myc: The Beauty and the Beast. Genes and Cancer 1(6): 532–541.

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Kalkat, Manpreet, and Penn, Linda Z(Nov 2013) Regulation and Function of the MYC Oncogene. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024149]