Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

• DOI: 10.3389/fonc.2021.615568
• Publication Date: 2021-02-23T05:26:12Z
• Authors: Zhengfang Liu; Cheng Liu; Keqiang Yan; Jikai Liu; Zhiqing Fang; Yidong Fan
• Keywords: Pulmonary and Respiratory Medicine; 0301 basic medicine; Ubiquitin-Proteasome Proteolytic Pathway; Cell biology; Carcinogenesis; androgen receptor splicing variant 7 (AR-V7); Cancer research; Androgen deprivation therapy; 03 medical and health sciences; Advancements in Prostate Cancer Research; 0302 clinical medicine; Biochemistry, Genetics and Molecular Biology; Health Sciences; Enzalutamide; full length androgen receptor (AR-FL); Molecular Biology; Biology; Internal medicine; RC254-282; Cancer; Chemotherapy-Induced Peripheral Neuropathy in Cancer Treatment; Prostate cancer; enzalutamide; Proteasome; Prostate Cancer; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Life Sciences; prostate cancer; 3. Good health; Androgen receptor; Chemistry; Oncology; Androgen Receptor; Medicine; huaier extract

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.