CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

Abstract

Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate <i>TP53</i> (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists <i>Prmt5, Ppm1d</i>, and <i>Mdm4</i> The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in <i>TP53</i> significantly more often than expected.<b>Significance:</b> CDK6 acts at the interface of p53 and RB by driving cell-cycle progression and antagonizing stress responses. While sensitizing cells to p53-induced cell death, specific inhibition of CDK6 kinase activity may provoke the outgrowth of p53-mutant clones from premalignant cells. <i>Cancer Discov; 8(7); 884-97. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 781</i>.