Zhang Ye, Xu Ying-Ying, Yao Chuan-Bo, Li Jin-Tao, Zhao Xiang-Ning, Yang Hong-Bin, Zhang Min, Yin Miao, Chen Jing, Lei Qun-Ying
a Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology , School of Basic Medical Sciences, and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, and State Key Laboratory of Medical Neurobiology, Fudan University , Shanghai , China.
b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory, Emory University School of Medicine , Atlanta , GA , USA.
Autophagy. 2017 Mar 4;13(3):538-553. doi: 10.1080/15548627.2016.1268302. Epub 2017 Feb 22.
Dysregulation of hormone metabolism is implicated in human breast cancer. 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) catalyzes the conversion of estradiol (E2) to estrone (E1), and is associated with the pathogenesis and development of various cancers. Here we show that E1 upregulates HSD17B4 acetylation at lysine 669 (K669) and thereby promotes HSD17B4 degradation via chaperone-mediated autophagy (CMA), while a single mutation at K669 reverses the degradation and confers migratory and invasive properties to MCF7 cells upon E1 treatment. CREBBP and SIRT3 dynamically control K669 acetylation level of HSD17B4 in response to E1. More importantly, K669 acetylation is inversely correlated with HSD17B4 in human breast cancer tissues. Our study reveals a crosstalk between acetylation and CMA degradation in HSD17B4 regulation, and a critical role of the regulation in the malignant progression of breast cancer.
激素代谢失调与人类乳腺癌有关。4型17β-羟基类固醇脱氢酶（HSD17B4）催化雌二醇（E2）转化为雌酮（E1），并与多种癌症的发病机制和发展相关。在此我们表明，E1上调HSD17B4赖氨酸669（K669）位点的乙酰化，从而通过伴侣介导的自噬（CMA）促进HSD17B4的降解，而K669位点的单个突变可逆转这种降解，并使MCF7细胞在E1处理后具有迁移和侵袭特性。CREBBP和SIRT3响应E1动态控制HSD17B4的K669乙酰化水平。更重要的是，K669乙酰化在人类乳腺癌组织中与HSD17B4呈负相关。我们的研究揭示了HSD17B4调控中乙酰化与CMA降解之间的相互作用，以及该调控在乳腺癌恶性进展中的关键作用。
