Abstract 320: Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects

Abstract Transcription factor MYC is a driver of many human cancers due to its widespread effects on gene expression. An understanding of the mechanisms determining MYC’s transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage-induced proliferation. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells or general well-being of the mice. Meanwhile, in breast cancer cells, CIP2A depletion was shown to inhibit the MYC serine 62 phosphorylation, MYC-mediated gene expression, and anchorage-independent growth. Furthermore, CIP2A supports MDA-MB-231 xenograft growth in nude mice. Therefore, results of these studies collectively suggest for a novel opportunity to target MYC’s function in MYC- driven cancers via CIP2A, and without detrimental physiological effects. Citation Format: Xi Qiao. Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2017-320