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Hepatocyte-generated 27-hydroxycholesterol promotes the growth of melanoma by activation of estrogen receptor alpha.

Authors
  • Tian, Wei1
  • Pang, Wenxiao1, 2
  • Ge, Yao1
  • He, Xiaomeng1
  • Wang, Duowei1
  • Li, Xianjing1
  • Hou, Hui1
  • Zhou, Dewang1
  • Feng, Shuang1
  • Chen, Zhen1
  • Yang, Yong1
  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, China. , (China)
  • 2 Infectious Disease Research Office, Public Health Clinical Center of Chengdu, Chengdu, China. , (China)
Type
Published Article
Journal
Journal of Cellular Biochemistry
Publisher
Wiley (John Wiley & Sons)
Publication Date
Mar 01, 2018
Volume
119
Issue
3
Pages
2929–2938
Identifiers
DOI: 10.1002/jcb.26498
PMID: 29130512
Source
Medline
Keywords
License
Unknown

Abstract

Cholesterol plays an important role in maintaining normal physiological function of human body. However, excessive intake will induce a series of diseases including cancer. For melanoma, the relationship between hypercholesterolemia and its incidence remains unknown. The cholesterol metabolite 27-hydroxy cholesterol (27-HC) catalyzed by CYP27A1 has been reported to activate estrogen receptor (ER). As studies have indicated that melanoma expresses ER, we designed experiments to explore whether 27-HC could link hypercholesterolemia and melanoma. In this study, hepatocyte-specific CYP27A1-/- mice were generated by CRISPR/Cas9 technology. The results revealed that high-cholesterol diet induced metabolism disorder and promoted the melanoma growth through 27-HC. Further study found that 27-HC promoted the growth of melanoma cells by activating ERα and eliciting the AKT and MAPK signaling pathway. This study puts forward the important role of 27-HC in the development of melanoma for the first time, links hypercholesterolemia with melanoma progression. The research also provides the rationale for the use of tamoxifen in melanoma therapy. The levels of 27-HC in blood could act as a novel biomarker for tamoxifen treatment in melanoma patients.

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