25-hydroxycholesterol down-regulates oxysterol binding protein like 2 (OSBPL2) via the p53/SREBF2/NFYA signaling pathway

Quan Wang; Changsong Lin; Cui Zhang; Hongshun Wang; Yajie Lu; Jun Yao; Qinjun Wei; Guangqian Xing; Xin Cao

doi:10.1016/j.jsbmb.2018.10.018

25-hydroxycholesterol down-regulates oxysterol binding protein like 2 (OSBPL2) via the p53/SREBF2/NFYA signaling pathway

J Steroid Biochem Mol Biol. 2019 Mar:187:17-26. doi: 10.1016/j.jsbmb.2018.10.018. Epub 2018 Nov 2.

Authors

Quan Wang¹, Changsong Lin¹, Cui Zhang¹, Hongshun Wang¹, Yajie Lu², Jun Yao², Qinjun Wei³, Guangqian Xing⁴, Xin Cao⁵

Affiliations

¹ Department of Medical Genetics, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China.
² Department of Medical Genetics, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, 211166, China.
³ Department of Medical Genetics, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, 211166, China; The Laboratory Center for Basic Medical Sciences, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China.
⁴ Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
⁵ Department of Medical Genetics, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, 211166, China; The Laboratory Center for Basic Medical Sciences, School of Basic Medicinal Sciences, Nanjing Medical University, Nanjing, 211166, China. Electronic address: caoxin@njmu.edu.cn.

PMID: 30391516
DOI: 10.1016/j.jsbmb.2018.10.018

Abstract

Oxysterol Binding Protein Like 2 (OSBPL2) is a lipid-binding protein implicated in various cellular processes. Previous studies have shown that depression of OSBPL2 significantly increases the level of cellular 25-hydroxycholesterol (25-OHC) which regulates the expression of lipid-metabolism-related genes. However, whether 25-OHC can regulate the expression of OSBPL2 remains unanswered. This study aimed to explore the molecular mechanism of 25-OHC regulating the expression of OSBPL2. Using dual-luciferase reporter assay, we found a decrease of nuclear transcription factor Y subunit alpha (NFYA) bound with OSBPL2 promoter when HeLa cells were treated with 25-OHC. Furthermore, transcriptome sequencing and RNA interference results revealed that the p53/sterol regulatory element binding transcription factor 2 (SREBF2) signaling pathway was involved in the NFYA-dependent transcription of OSBPL2 induced by 25-OHC. Based on these results, we concluded that pleomorphic adenoma gene 1 (PLAG1) and NFYA participated in the basal transcription of OSBPL2 and that 25-OHC decreased the transcription of OSBPL2 via the p53/SREBF2/NFYA signaling pathway. 25-OHC will accumulate over time in OSBPL2 knockdown cells. These results may provide a new insight into the deafness caused by OSBPL2 mutation.

Keywords: 25-hydroxycholesterol; Cholesterol/synthesis and regulation; NFYA; OSBPL2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CCAAT-Binding Factor / metabolism*
Down-Regulation*
HeLa Cells
Humans
Hydroxycholesterols / metabolism*
Promoter Regions, Genetic
Receptors, Steroid / genetics*
Signal Transduction*
Sterol Regulatory Element Binding Protein 2 / metabolism*
Tumor Suppressor Protein p53 / metabolism*

Substances

CCAAT-Binding Factor
Hydroxycholesterols
NFYA protein, human
OSBPL2 protein, human
Receptors, Steroid
SREBF2 protein, human
Sterol Regulatory Element Binding Protein 2
Tumor Suppressor Protein p53
25-hydroxycholesterol