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Protein Kinase N1 control of androgen-responsive serum response factor action provides rationale for novel prostate cancer treatment strategy

Oncogene volume 38, pages 4496–4511 (2019)Cite this article

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Abstract

Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1’s effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR’s transcriptional output to inhibit CaP growth.

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Acknowledgements

The authors thank Dr. Cassandra Talerico for review of the manuscript and Heemers lab members for helpful discussions. RNA-Seq was supported by NCI grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Genomic Shared Resource.

Financial support

These studies were supported by DOD PCRP award W81XWH-16–1–0404 (HVH), NIH NCI grants CA166440 (HVH), CA174777 (SMD), CA077739 (JLM), CA232979 (SL) and CA016056 (JLM and SL).

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Authors and Affiliations

  1. Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA

    Varadha Balaji Venkadakrishnan, Sangeeta Kumari, Dhirodatta Senapati, Salma Ben-Salem, Yixue Su, Giridhar Mudduluru, Nima Sharifi & Hannelore V. Heemers

  2. Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, USA

    Varadha Balaji Venkadakrishnan

  3. Department of Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Adam D. DePriest

  4. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Qiang Hu, Eduardo Cortes, Kristopher Attwood & Song Liu

  5. Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Elena Pop, James L. Mohler & Gissou Azabdaftari

  6. Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Gissou Azabdaftari

  7. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA

    Rajal B. Shah & Cristina Magi-Galluzzi

  8. Department of Urology, University of California, San Diego, LaJolla, CA, USA

    Christina Jamieson

  9. Masonic Cancer Center and Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA

    Scott M. Dehm

  10. Department of Urology, Cleveland Clinic, Cleveland, OH, USA

    Eric Klein, Nima Sharifi & Hannelore V. Heemers

  11. Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, OH, USA

    Nima Sharifi & Hannelore V. Heemers

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  1. Varadha Balaji Venkadakrishnan
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Venkadakrishnan, V.B., DePriest, A.D., Kumari, S. et al. Protein Kinase N1 control of androgen-responsive serum response factor action provides rationale for novel prostate cancer treatment strategy. Oncogene 38, 4496–4511 (2019). https://doi.org/10.1038/s41388-019-0732-7

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