眾所周知，雄激素受體對于前列腺癌的發(fā)生和發(fā)展至關重要。還有文獻表明，雄激素受體表達于60%以上的乳腺腫瘤，可以促進雌激素受體陰性、雄激素受體陽性乳腺癌細胞的生長。因此，雄激素受體可能是雄激素受體陽性、雌激素受體陰性乳腺癌患者的潛在治療靶點。
2018年1月22日，英國《自然》旗下《癌基因》在線發(fā)表廣州醫(yī)科大學及其附屬腫瘤醫(yī)院、第二醫(yī)院、第三醫(yī)院、美國韋恩州立大學、芭芭拉·安·卡馬諾斯癌癥研究所、匹茲堡大學的研究報告，發(fā)現(xiàn)通過抑制雄激素受體去泛素酶，可使雄激素受體陽性乳腺癌細胞凋亡并停止生長。
作者既往研究發(fā)現(xiàn)，前列腺癌細胞蛋白酶體相關去泛素酶：泛素特異蛋白酶14（USP14）通過去除泛素鏈可以穩(wěn)定雄激素受體蛋白水平。
此次，作者對USP14與雄激素受體蛋白的相互影響、乳腺癌細胞USP14被減少或抑制后的細胞增殖狀態(tài)進行了研究，結果證實USP14靶向療法可以成為治療雄激素受體陽性乳腺癌的新策略。
該研究發(fā)現(xiàn)抑制USP14可以加速K48泛素化以及蛋白酶體所致雄激素受體蛋白降解。此外，對USP14進行遺傳學和藥理學抑制，阻斷雄激素受體陽性乳腺癌細胞G0/G1→S期轉(zhuǎn)化并誘導凋亡，可以顯著抑制細胞增殖。而且，雄激素受體過表達還可抑制USP14受抑所致乳腺癌細胞凋亡和生長停滯，表明USP14的雄激素受體去泛素化作用對于乳腺癌生長至關重要，并且抑制USP14可能成為雄激素受體陽性乳腺癌治療新策略。
Oncogene. 2018 Jan 22. [Epub ahead of print]
Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination.
Yuning Liao, Xiaohong Xia, Ningning Liu, Jianyu Cai, Zhiqiang Guo, Yanling Li, Lili Jiang, Q. Ping Dou, Daolin Tang, Hongbiao Huang, Jinbao Liu.
Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China; Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA; Wayne State University, Detroit, MI, USA; Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; University of Pittsburgh, Pittsburgh, PA, USA.
It has been well known that androgen receptor (AR) is critical to prostate cancer development and progression. It has also been documented that AR is expressed in more than 60% of breast tumors, which promotes the growth of estrogen receptor-negative (ER-)/AR-positive (AR+) breast cancer cells. Thus, AR might be a potential therapeutic target for AR-positive/ER-negative breast cancer patients. Previously we reported that in prostate cancer cells proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) stabilized AR protein level by removing its ubiquitin chain. In the current study, we studied the USP14-AR protein interaction and cell proliferation status after USP14 reduction or inhibition in breast cancer cells, and our results support the conclusion that targeting USP14 is a novel strategy for treating AR-responsive breast cancer. We found that inhibition of USP14 accelerated the K48-ubiquitination and proteasome-mediated degradation of AR protein. Additionally, both genetic and pharmacological inhibition of USP14 significantly suppressed cell proliferation in AR-responsive breast cancer cells by blocking G0/G1 to S phase transition and inducing apoptosis. Moreover, AR overexpression inhibited USP14 inhibition-induced events, suggesting that AR deubiquitination by USP14 is critical for breast cancer growth and USP14 inhibition is a possible strategy to treat AR-positive breast cancer.
DOI: 10.1038/s41388-017-0069-z
