Controlling the Master: Chromatin Dynamics at the MYC Promoter Integrate Developmental Signaling

Abstract

The transcription factor and cell growth regulator MYC is potently oncogenic and estimated to contribute to most cancers. Decades of attempts to therapeutically target MYC directly have not resulted in feasible clinical applications, and efforts have moved toward indirectly targeting MYC expression, function and/or activity to treat MYC-driven cancer. A multitude of developmental and growth signaling pathways converge on the MYC promoter to modulate transcription through their downstream effectors. Critically, even small increases in MYC abundance (<2 fold) are sufficient to drive overproliferation; however, the details of how oncogenic/growth signaling networks regulate MYC at the level of transcription remain nebulous even during normal development. It is therefore essential to first decipher mechanisms of growth signal-stimulated MYC transcription using in vivo models, with intact signaling environments, to determine exactly how these networks are dysregulated in human cancer. This in turn will provide new modalities and approaches to treat MYC-driven malignancy. Drosophila genetic studies have shed much light on how complex networks signal to transcription factors and enhancers to orchestrate Drosophila MYC (dMYC) transcription, and thus growth and patterning of complex multicellular tissue and organs. This review will discuss the many pathways implicated in patterning MYC transcription during development and the molecular events at the MYC promoter that link signaling to expression. Attention will also be drawn to parallels between mammalian and fly regulation of MYC at the level of transcription.

Transcriptional repression of Myc underlies AGO1’s tumour suppressor function

“…In normal adult tissues, MYC expression is relatively low and generally restricted to cells with regenerative and proliferative potential (Marcu et al, 1992). Even small increases in MYC abundance are sufficient to promote proliferative cell growth (reviewed in (Dang, 2010;Levens, 2010;Zaytseva and Quinn, 2017)), thus, understanding the molecular control of MYC expression will provide critical insight into mechanisms of MYC dysregulation in cancer.…”

Targeting Developmental Pathways: The Achilles Heel of Cancer?

“…In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway [1] .…”

“…Information of this sort is now becoming available with remarkable resolution and several operating principles seem to be emerging: (1) pathways, not just genes, are conserved from model systems (e.g., Drosophila ) to analogous systems (mouse and rat) and humans; (2) the pathways make use of several levels of regulation, i.e., transcription, translation, and post-translation; (3) relatively few genes are involved in a combinatorial manner in forming complex pathways; and (4) transcription factors are determinedly used to create a pattern for the development of the body plan [1] .…”

“…The key to establishing which genes are at risk of which exposures lies in understanding the underlying molecular biology of these critical pathways [1,2] .…”

MYC in Brain Development and Cancer

“…The MYC family of basic helix-loop-helix (bHLH) transcription factors, comprised of MYC, MYCN and MYCL, are central to cell fate decisions, controlling transcriptional networks that govern cell growth, division, differentiation and death (reviewed in [ 1 , 2 , 3 , 4 , 5 ]). The expression of MYC family genes is tightly regulated during development in order to ensure high expression in proliferative stem and progenitor cells and downregulation in differentiated daughters [ 6 ].…”