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Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer

Oncogene volume 42, pages 2126–2138 (2023)Cite this article

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Abstract

The hormonal transcription factor androgen receptor (AR) is a master regulator of prostate cancer (PCa). Protein palmitoylation, which attaches a palmitate fatty acid to a substrate protein, is mediated by a class of 23 ZDHHC (Zinc-Finger DHHC motif)-family palmitoyltransferases. Although palmitoylation has been shown to modify many proteins and regulate diverse cellular processes, little is known about ZDHHC genes in cancer. Here we examined ZDHHC family gene expression in human tissue panels and identified ZDHHC7 as a PCa-relevant member. RNA-seq analyses of PCa cells with ZDHHC7 de-regulation revealed global alterations in androgen response and cell cycle pathways. Mechanistically, ZDHHC7 inhibits AR gene transcription and therefore reduces AR protein levels and abolishes AR signaling in PCa cells. Accordingly, ZDHHC7 depletion increased the oncogenic properties of PCa cells, whereas restoring ZDHHC7 is sufficient to suppress PCa cell proliferation and invasion in vitro and mitigate xenograft tumor growth in vivo. Lastly, we demonstrated that ZDHHC7 is downregulated in human PCa compared to benign-adjacent tissues, and its loss is associated with worse clinical outcomes. In summary, our study reveals a global role of ZDHHC7 in inhibiting androgen response and suppressing PCa progression and identifies ZDHHC7 loss as a biomarker for aggressive PCa and a target for therapeutic intervention.

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Fig. 1: ZDHHC7 is a PCa-relevant ZDHHC family gene.
Fig. 2: ZDHHC7 overexpression attenuates androgen response and cell cycle in PCa cells.
Fig. 3: ZDHHC7 knockdown promotes androgen response and cell cycle in PCa cells.
Fig. 4: ZDHHC7 does not alter AR protein localization but reduces total AR protein levels.
Fig. 5: ZDHHC7 regulates AR, AR-V7, and their target gene transcription.
Fig. 6: ZDHHC7 inhibits PCa cell growth and invasion in vitro and in vivo.
Fig. 7: ZDHHC7 is downregulated in PCa, and its low expression predicts a poor prognosis.

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Data availability

All next-generation sequencing data have been uploaded to the GEO database under GSE222592.

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Funding

This work was supported by the DOD grants PC160759 (to XW) and PC160759P1 (to JY) and Prostate Cancer Foundation 2017CHAL2008 (to JY, JCZ). We thank Baoen Chen (MGH), Carla Guarino (MGH), Viriya Keo (NU), and Ka-Wing Fong (NU) for their technical assistance.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Zhuoyuan Lin, Shivani Agarwal, Song Tan, Hongshun Shi, Xiaodong Lu, Jonathan C. Zhao & Jindan Yu

  2. Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Zhuoyuan Lin

  3. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Zhipeng Tao & Xu Wu

  4. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

    Xuesen Dong

  5. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Jindan Yu

  6. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA

    Jindan Yu

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  1. Zhuoyuan Lin
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Contributions

JY and ZL conceived the project. ZL, SA, ST, XL, ZT, and HS designed and performed the experiments. XD performed TMA of ZDHHC7. JCZ conducted bioinformatics and statistical analysis. ZL, SA, JCZ, and JY generated the figures and wrote the manuscript. XW provided critical discussions. All authors read the manuscript.

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Correspondence to Jindan Yu.

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Lin, Z., Agarwal, S., Tan, S. et al. Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer. Oncogene 42, 2126–2138 (2023). https://doi.org/10.1038/s41388-023-02718-2

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