Repression of SLC22A3 by the AR‐V7/YAP1/TAZ axis in enzalutamide‐resistant castration‐resistant prostate cancer

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Abstract
Metastatic castration‐resistant prostate cancer (mCRPC) is an aggressive and fatal disease, with most patients succumbing within 1–2 years despite undergoing multiple treatments. Androgen‐receptor (AR) inhibitors, including enzalutamide (ENZ), are used for the treatment of mCRPC; however, most patients develop resistance to ENZ. Herein, we propose that the repression of SLC22A3 by AR‐V7/YAP1/TAZ conferred ENZ resistance in mCRPC. SLC22A3 expression is specifically downregulated in the ENZ‐resistant C4‐2B MDVR cells, and when YAP1/TAZ is hyperactivated by AR full‐length or AR‐V7, these proteins interact with DNMT1 to repress SLC22A3 expression. We observed low SLC22A3 expression and high levels of TAZ or YAP1 in mCRPC patient tissues harbouring AR‐V7 and the opposite expression patterns in normal patient tissues. Our findings suggest a mechanism underlying ENZ resistance by providing evidence that the AR‐V7/YAP1/TAZ axis represses SLC22A3, which could be a potential treatment target in prostate cancer.
Funding Information
  • National Research Foundation of Korea (2022R1A2C1010038, NRF‐2020R1A2C2007662, NRF‐2020R1C1C1005054, NRF‐2021R1I1A1A01040437, NRF2016R1D1A1B01012138)

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