CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

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 TP53 (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists Prmt5, Ppmld, and Mdm4. The findings are relevant to human patients:Tumors with low levels of CDK6 have mutations in TP53 significantly more often than expected. SIGNIFICANCE: 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. (C)2018 AACR. 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 TP53 (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists Prmt5, Ppm1d, and Mdm4 The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in TP53 significantly more often than expected.Significance: 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. Cancer Discov; 8(7); 884-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.©2018 American Association for Cancer Research.

• CDK6 as regulator of DNA methylation and transcription: CDK6: structure function.
• STAT5A and STAT5B in Hematopoiesis and Leukemogenesis.

Brigham & Womens Hosp
CNIO Spanish Natl Canc Res Ctr
Dana-Farber Cancer Institute
Tufts Univ
CeMM Center for Molecular Medicine of the Austrian Academy of Sciences
MLL Münchner Leukämielabor GmbH
Medizinische Universität Innsbruck
Medizinische Universität Wien - AKH
Österreichische Akademie der Wissenschaften
Research Institute of Molecular Pathology
Veterinärmedizinische Universität Wien
Tufts University, School of Medicine, Department of Physiology
Tufts Canc Ctr
Centro Nacional de Investigaciones Oncologicas (CNIO)
Vienna Biocenter
Tufts University
Harvard University