Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

<p>Dysregulation of hormone metabolism is implicated in human breast cancer. 17β-hydroxysteroid dehydrogenase type 4 (<i>HSD17B4</i>) 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 <i>HSD17B4</i> acetylation at lysine 669 (K669) and thereby promotes <i>HSD17B4</i> 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 <i>HSD17B4</i> in response to E1. More importantly, K669 acetylation is inversely correlated with <i>HSD17B4</i> in human breast cancer tissues. Our study reveals a crosstalk between acetylation and CMA degradation in <i>HSD17B4</i> regulation, and a critical role of the regulation in the malignant progression of breast cancer.</p>