KDM5B cooperates with CRL4B complex to promote the tumorigenesis of ER+ breast cancer via regulating cholesterol metabolism

TL;DR

This study shows how KDM5B and CRL4B work together to control cholesterol metabolism in ER+ breast cancer, promoting tumor growth and suggesting new treatment strategies.

Contribution

The study identifies a novel regulatory axis between KDM5B and CRL4B in cholesterol metabolism to drive ER+ breast cancer progression.

Findings

KDM5B interacts with CRL4B to regulate cholesterol metabolism genes INSIG1 and INSIG2 in ER+ breast cancer.

Disruption of the KDM5B–CRL4B axis impairs cholesterol homeostasis and inhibits tumor growth.

KDM5B upregulation is negatively correlated with survival rates in multiple cancer types.

Abstract

Estrogen receptor-positive (ER+) breast cancer is the predominant subtype of breast cancer, and its development is closely linked to metabolic reprogramming, including alterations in cholesterol metabolism. Therefore, this study aimed to investigate the functional interplay between lysine demethylase 5B (KDM5B) and the Cullin-RING ligase 4B (CRL4B) complex in modulating cholesterol metabolism to promote ER+ breast cancer progression. Immunohistochemical assays and bioinformatic analysis of various cancer databases were performed to examine KDM5B expression levels in breast cancer. Additionally, KDM5B overexpression and knockdown were performed to investigate the role of KDM5B in breast cancer cell proliferation and progression. Notably, we identified physical and functional interactions between KDM5B and the CRL4B subunits, CUL4B and DDB1. Mechanistically, KDM5B recruits CRL4B to the promoters of INSIG1 and INSIG2, which are key regulators of cholesterol biosynthesis and uptake, and suppresses their expression by upregulating H2AK119ub1 and downregulating H3K4me3 histone marks, thereby promoting the proliferation, migration, and invasion of tumor cells. Functional assays revealed that disruption of the KDM5B–CRL4B axis impairs cholesterol homeostasis and inhibits tumor growth. KDM5B upregulation was significantly negatively correlated with the survival rates in various cancer types, including thyroid, lung, esophageal and colorectal cancers. Overall, these findings establish a novel regulatory axis in cholesterol metabolism, uncover potential therapeutic vulnerabilities in ER+ breast cancer, and suggest that targeting the KDM5B could provide a strategy to curb tumor progression.

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