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. 2023 Mar;290(6):1645-1662.
doi: 10.1111/febs.16657. Epub 2022 Oct 30.

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

Eunjeong Seo  1 , Byula Jee  1 , Jae Hoon Chung  1 , Wan Song  1 , Hyun Hwan Sung  1 , Hwang Gyun Jeon  1 , Byong Chang Jeong  1 , Seong Il Seo  1 , Seong Soo Jeon  1 , Hyun Moo Lee  1 , Minyong Kang  1   2   3
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Free article

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

Eunjeong Seo et al. FEBS J. 2023 Mar.
Free article

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.

Keywords: AR-V7; SLC22A3; TAZ; YAP1; enzalutamide resistance.

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