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

Ye Zhang1, Ying-Ying Xu1, Chuan-Bo Yao1

  • 1a 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.

Autophagy
|March 16, 2017
PubMed

Insights

Estrone (E1) triggers acetylation of 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4), promoting its degradation. This regulation is crucial for breast cancer progression and is inversely correlated with HSD17B4 levels in patient tissues.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Hormone metabolism dysregulation is linked to breast cancer pathogenesis.
  • 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) enzyme activity is associated with cancer development.

Purpose of the Study:

  • To investigate the regulatory mechanism of HSD17B4 by estrone (E1).
  • To elucidate the role of HSD17B4 acetylation and degradation in breast cancer malignancy.

Main Methods:

  • Investigated HSD17B4 acetylation at lysine 669 (K669) in response to E1.
  • Utilized cell culture (MCF7) and mutation analysis to assess HSD17B4 function.
  • Examined the involvement of chaperone-mediated autophagy (CMA) in HSD17B4 degradation.
  • Analyzed CREBBP and SIRT3 roles in regulating K669 acetylation.
  • Correlated K669 acetylation with HSD17B4 expression in human breast cancer tissues.

Main Results:

  • Estrone (E1) upregulates HSD17B4 acetylation at K669, leading to its degradation via chaperone-mediated autophagy (CMA).
  • A K669 mutation prevents degradation, conferring migratory and invasive properties to MCF7 cells upon E1 treatment.
  • CREBBP and SIRT3 modulate HSD17B4 K669 acetylation levels dynamically.
  • K669 acetylation is inversely correlated with HSD17B4 protein levels in human breast cancer tissues.

Conclusions:

  • A novel regulatory pathway involving HSD17B4 acetylation and CMA-mediated degradation is identified.
  • This acetylation-mediated regulation of HSD17B4 plays a critical role in breast cancer malignant progression.
  • Findings highlight a significant crosstalk between protein acetylation and autophagy in hormone-driven cancers.
Keywords:
HSD17B4acetylationcancerchaperone-mediated autophagyestrone

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