A CDCA2 - MYC positive feedback loop controls cancer cells survival

Abstract

MYC transcription factors are encoded by a small family of genes which include, in addition to the prototype member MYC, MYCN and MYCL. The majority of human cancers display expression alterations of MYC genes and their products, making this group of oncoproteins among the most relevant therapeutic targets in oncology. MYC is regulated at multiple levels, and protein phosphorylation is a critical mechanism used by the cell to modulate MYC stability and activity. Although there is a reasonable knowledge of the kinases required for MYC modifications, the counteracting phosphatases have been relatively understudied. Here we have investigated the role of the chromatin remodelling factor and protein phosphatase 1 (PP1) regulatory subunit CDCA2, also known as RepoMan, in the regulation of MYC proteins in cancer cells. Using RNA interference and regulatable degron-mediated degradation of CDCA2, we demonstrate that the PP1 subunit is required for MYC and MYCN stabilisation and viability of triple negative breast cancer, neuroblastoma and colon cancer cells. Proximity ligation assays indicate that both MYC and MYCN are in close proximity of CDCA2 in vivo. Furthermore, chromatin immunoprecipitation data and promoter mutation studies establish that CDC2A is a bone-fide MYC target gene in cancer cells, revealing a reciprocal regulatory loop that could be exploited for therapeutic purposes.