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YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells

Oncogene volume 38, pages 5541–5550 (2019)Cite this article

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Abstract

The oncogene yes-associated protein (YAP) is a key modifier of liver homeostasis and regulates mitosis in hepatocytes as well as in malignantly transformed cells. However, the question of how YAP supports cell proliferation in hepatocellular carcinoma (HCC) is not well understood. Here we identified U2AF momology motif kinase 1 (UHMK1) as a direct transcriptional target of YAP and the transcription factor forkhead box M1 (FOXM1), which supports HCC cell proliferation but not migration. Indeed, UHMK1 stimulates the expression of genes that are specific for cell cycle regulation and which are known downstream effectors of YAP. By using BioID labeling and mass spectrometry, the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex constituent MYB proto-oncogene like 2 (MYBL2, B-MYB) was identified as a direct UHMK1 interaction partner. Like YAP, UHMK1 stimulates nuclear enrichment of MYBL2, which is associated HCC cell proliferation and the expression of the cell cycle regulators CCNB1, CCNB2, KIF20A, and MAD2L1. The association between YAP, UHMK1, MYBL2, and proliferation was confirmed in YAPS127A-transgenic mice and human HCC tissues. In summary, we provide a model by which YAP supports cell proliferation through the induction of important cell cycle regulators in a UHMK1- and MYBL2-dependent manner.

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Acknowledgements

We thank M. Bissinger and J. Schmitt for excellent technical assistance, Dr. A. Ori for providing us with the BirA vector, as well as T. R. Brummelkamp and F. D. Camargo for providing Col1A1-YAPS127A transgenic mice. Tissue samples were provided by the tissue bank of the National Center of Tumor Diseases (Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the Ethics Committee of Heidelberg University. We also thank the Center of Model System and Comparative Pathology (CMCP; Dr. F. Lasitschka, Dr. T. Poth) and H. Conrad for their support. This study was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe/Dr. Mildred Scheel Stiftung, to K.B., DKH 111524), the SFB/TR 209 “Liver Cancer” (to K.B., S.S., and P.S.), the priority program SPP1782/2 (to K.B.), and the China Scholarship Council/CSC (to T.W.). J.U.M. is supported by grants from the German Research Foundation (MA 4443/2-2) and the Volkswagen Foundation (Lichtenberg program).

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Authors and Affiliations

  1. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Teng Wei, Sofia Maria Elisabeth Weiler, Marcell Tóth, Teresa Lutz, Stefan Thomann, Peter Schirmacher & Kai Breuhahn

  2. Medical Faculty Mannheim, Medical Research Center, University of Heidelberg, Mannheim, Germany

    Carsten Sticht, Carolina De La Torre & Norbert Gretz

  3. Institute of Pathology, Johannes Gutenberg University, Mainz, Germany

    Beate Straub

  4. Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany

    Sabine Merker & Thomas Ruppert

  5. Department of Medicine I, Johannes Gutenberg University, Mainz, Germany

    Jens Marquardt

  6. Institute of Pathology, University Medicine Greifswald, Greifswald, Germany

    Stephan Singer

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  1. Teng Wei
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Wei, T., Weiler, S.M.E., Tóth, M. et al. YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells. Oncogene 38, 5541–5550 (2019). https://doi.org/10.1038/s41388-019-0801-y

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