title: Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Chuan-Bo
authors.initials: CB
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Jin-Tao
authors.initials: JT
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiang-Ning
authors.initials: XN
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Miao
authors.initials: M
authors.lastname: Yin
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory, Emory University School of Medicine , Atlanta , GA , USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
mesh_terms: D000107:Acetylation; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004970:Estrone / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D064029:Peroxisomal Multifunctional Protein-2 / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D056566:Sirtuin 3 / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D004970:Estrone; D050882:CREB-Binding Protein; D056566:Sirtuin 3; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D008239:Lysine
keywords: HSD17B4; acetylation; cancer; chaperone-mediated autophagy; estrone