Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release

Author:

Wang Zhijia1ORCID,Himanen Samu V2ORCID,Haikala Heidi M34ORCID,Friedel Caroline C5ORCID,Vihervaara Anniina2ORCID,Barborič Matjaž1ORCID

Affiliation:

1. Department of Biochemistry and Developmental Biology, University of Helsinki , Helsinki  FIN-00014 , Finland

2. Department of Gene Technology, KTH Royal Institute of Technology, Science for Life Laboratory , Stockholm , Sweden

3. Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of Helsinki , Helsinki  FIN-00014 , Finland

4. iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki , Helsinki  FIN-00014 , Finland

5. Institute of Informatics, Ludwig-Maximilians-Universität München , 80333  Munich , Germany

Abstract

Abstract P-TEFb and CDK12 facilitate transcriptional elongation by RNA polymerase II. Given the prominence of both kinases in cancer, gaining a better understanding of their interplay could inform the design of novel anti-cancer strategies. While down-regulation of DNA repair genes in CDK12-targeted cancer cells is being explored therapeutically, little is known about mechanisms and significance of transcriptional induction upon inhibition of CDK12. We show that selective targeting of CDK12 in colon cancer-derived cells activates P-TEFb via its release from the inhibitory 7SK snRNP. In turn, P-TEFb stimulates Pol II pause release at thousands of genes, most of which become newly dependent on P-TEFb. Amongst the induced genes are those stimulated by hallmark pathways in cancer, including p53 and NF-κB. Consequently, CDK12-inhibited cancer cells exhibit hypersensitivity to inhibitors of P-TEFb. While blocking P-TEFb triggers their apoptosis in a p53-dependent manner, it impedes cell proliferation irrespective of p53 by preventing induction of genes downstream of the DNA damage-induced NF-κB signaling. In summary, stimulation of Pol II pause release at the signal-responsive genes underlies the functional dependence of CDK12-inhibited cancer cells on P-TEFb. Our study establishes the mechanistic underpinning for combinatorial targeting of CDK12 with either P-TEFb or the induced oncogenic pathways in cancer.

Funder

Sigrid Juselius Foundation

Academy of Finland

Cancer Foundation Finland

Deutsche Forschungsgemeinschaft

Swedish Research Council

Science for Life Laboratory

Helsinki University Library

Publisher

Oxford University Press (OUP)

Subject

Genetics

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