MYC Activation Is a Hallmark of Cancer Initiation and Maintenance
TLDR
Tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms.Abstract:
The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.read more
Citations
More filters
Journal ArticleDOI
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Jing Lu,Yimin Qian,Martha Altieri,Hanqing Dong,Jing Wang,Kanak Raina,John Hines,James D. Winkler,Andrew P. Crew,Kevin Coleman,Craig M. Crews +10 more
TL;DR: ARV-825 is designed, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation ofBRD4 in all BL cell lines tested.
Journal ArticleDOI
MYC: connecting selective transcriptional control to global RNA production
TL;DR: It is argued that differential gene regulation by MYC is the sole unifying model that is consistent with all available data and endow MYC with its pervasive oncogenic potential.
Journal ArticleDOI
Hallmarks of cancer stem cell metabolism.
TL;DR: Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients’ long-term outcome.
Journal ArticleDOI
Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis.
Marion Mussbacher,Manuel Salzmann,Christine Brostjan,Bastian Hoesel,Christian Schoergenhofer,Hannes Datler,Philipp J. Hohensinner,José Basílio,Peter Petzelbauer,Alice Assinger,Johannes A. Schmid +10 more
TL;DR: The role of NF-κB signaling in cell types within the vasculature and the circulation that are involved in thrombo-inflammatory processes is focused on, as it is critically involved in pathophysiological processes as it induces both inflammatory and thrombotic responses.
Journal ArticleDOI
An Overview of MYC and Its Interactome
TL;DR: A view of MYC as a sensor that integrates multiple cellular signals to mediate a broad transcriptional response controlling many aspects of cell behavior is presented and evidence that the network has evolved for millions of years, dating back to the emergence of animals is discussed.
References
More filters
Journal ArticleDOI
Immunity, Inflammation, and Cancer
TL;DR: The principal mechanisms that govern the effects of inflammation and immunity on tumor development are outlined and attractive new targets for cancer therapy and prevention are discussed.
Journal ArticleDOI
Selective inhibition of BET bromodomains.
Panagis Filippakopoulos,Jun Qi,Sarah Picaud,Yao Shen,William B. Smith,Oleg Fedorov,Elizabeth M. Morse,T. Keates,Tyler T. Hickman,I. Felletar,Martin Philpott,Shonagh Munro,Michael R. McKeown,Yuchuan Wang,Amanda L. Christie,Nathan West,Michael J. Cameron,Brian E. Schwartz,Tom D. Heightman,Nicholas B. La Thangue,Christopher A. French,Olaf Wiest,Andrew L. Kung,Stefan Knapp,Stefan Knapp,James E. Bradner +25 more
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Journal ArticleDOI
Induction of apoptosis in fibroblasts by c-myc protein
Gerard I. Evan,Andrew H. Wyllie,Christopher S. Gilbert,Trevor Littlewood,Hartmut Land,Mary W. Brooks,Catherine M. Waters,Linda Z. Penn,David C. Hancock +8 more
TL;DR: It is demonstrated that deregulated c-myc expression induces apoptosis in cells growth arrested by a variety of means and at various points in the cell cycle.
Journal ArticleDOI
MYC on the Path to Cancer
TL;DR: The richness of the understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies.
Journal ArticleDOI
BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
Related Papers (5)
BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more