Cancer initiation and progression is often driven by dysregulation of the Myc oncoprotein. The tumorigenic consequences of aberrant Myc expression emerge from its potential to broadly regulate gene expression. Alterations in gene expression resulting from specific epigenetic modifications contribute to the Myc oncogenic program to facilitate tumor development. As such, inhibitors targeting a certain class of chromatin-modifying enzymes have demonstrated therapeutic potential in treating malignancies, resulting in selective killing of cancer cells. However, the molecular events underlying the tumor cell-selective apoptosis are incompletely resolved. We determined that inhibition of specific epigenetic-modifying enzymes in cancers of hematopoietic and non-hematopoietic origin relieved the Myc-mediated transcriptional repression of specific genes. This transcriptional switch resulted in Myc-driven upregulation of these genes, which subsequently decreased the expression of crucial pro-survival genes, inducing apoptosis in multiple cancers. Furthermore, we demonstrated that Myc transcriptionally upregulated these genes in normal cells as a means to prevent cellular transformation, revealing a mechanism whereby Myc induces apoptosis independent of the p53 tumor suppressor. Our data reveal a Myc-regulated mechanism of cell death that underlies the apoptotic consequences of inhibiting a class of epigenetic modifiers. This apoptotic mechanism offers new insights that should aid in improving therapies for the 70% of human cancers that have dysregulated MYC.

Note: This abstract was not presented at the conference.

Citation Format: Clare M. Adams, Christine M. Eischen. Epigenetic alterations reactivate a novel mechanism of Myc-induced apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A14.

©2015 American Association for Cancer Research.
2015