A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

Karoline Kollmann,Veronika Sexl,Wolfgang Warsch,Richard Moriggl,Marcos Malumbres,Michael Freissmuth,Sabine Fajmann,Gerwin Heller,Lukas Kenner,Meinrad Busslinger,Ursula Reichart,Ruth Scheicher,Matthias Mayerhofer,Dontscho Kerjaschki,Markus Schäfer,Michaela Schlederer,Christine Schneckenleithner,Christoph Bock,Ana‐Iris Schiefer ,René G Ott ,Christoph Höeller ,Gerald Höefler ,Sabine Zöchbauer‐Müller ,Anthony Green

doi:10.1016/j.ccr.2013.07.012

Abstract

SummaryIn contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6’s kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6’s central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16INK4a.

Highlights

Cell cycle deregulation is a common feature of human cancer (Cordon-Cardo, 1995; Deshpande et al, 2005; Kim and Diehl, 2009; Malumbres and Barbacid, 2001)
Forced CDK6 Expression Suppresses Tumor Formation To investigate the consequences of increasing CDK6 expression in B-lymphoid leukemia/lymphoma, we generated stable p185BCR-ABL-transformed pro B cell lines
CDK6 Acts as a Transcriptional Regulator on the p16INK4a Promoter To investigate the underlying mechanism, we examined the expression of several genes known to be important for cell-cycle control

Summary

Introduction

Cell cycle deregulation is a common feature of human cancer (Cordon-Cardo, 1995; Deshpande et al, 2005; Kim and Diehl, 2009; Malumbres and Barbacid, 2001). Cell-cycle kinases represent promising targets for the development of low-molecular-weight compounds for use in cancer therapy (Cicenas and Valius, 2011; Malumbres, 2012). The cyclin-dependent kinase CDK6 promotes cell-cycle progression and is expressed at high levels in lymphoid tumors. We present evidence for a function of CDK6 as a transcriptional regulator that is unrelated to its kinase activity. Part of the CDK6-dependent gene signature is VEGF-A, which promotes tumor angiogenesis and controls de novo formation of blood vessels. CDK6 represents a factor that regulates tumor growth while ensuring the supply of oxygen and energy to the tumor. Available anticancer drugs targeting CDK6 focus on CDK6’s kinase-dependent functions. Our insights may reshape future strategies to develop CDK6 inhibitors, allowing the simultaneous inhibition of cell-cycle progression and CDK6’s other, kinase-independent functions

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Discussion

Conclusion