Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers

Abstract

Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.

Keywords: cancer; liver X receptor α; therapy; tumorigenesis.

Figure 1

Classical mechanism and multifarious ligands of LXRα. The classical transcriptional mechanism of LXRα is binding to RXR formatting heterodimer. When the LXRα/RXR interacts with corepressors, LXRα/RXR dimer activation is inhibited, and transcription of the target genes is suspended. Once the corepressor is dissociated, the ligands could activate the function of LXRα/RXR to interact with LXRE (AGGTCAnnnnAGGTCA) located in the promoter of target genes and regulate the transcription of target genes. Some ligands are depicted here, including agonists and antagonists.

Figure 2

LXRα expression levels in different types of human cancers: (A) increased or decreased expression of LXRα in different types of cancer tissues compared with normal tissues in the Oncomine database; (B) human LXRα expression levels in different cancers were assessed using the TIMER 2.0 database (** p < 0.01, and *** p < 0.001).

Figure 3

Biological function and mechanisms of LXRα in various cancers. LXRα is related to the carcinogenesis of different cancers, including glioblastoma, liver, lung, stomach, kidney, colon, pancreas, prostate, breast, and other cancers depicted in the figure. LXRα mainly exerts function in cancer cells via the Wnt/β-catenin, NF-κB, EGFR/ERK, and TGFβ signaling pathways to regulate cell differentiation, migration, invasion, EMT, and apoptosis. Moreover, the activation of LXRα also modulates target genes, such as NLRP3, PPARγ, SREBF-1c, ABCA1, and other targets, leading to proliferation inhibition, cell cycle arrest, DNA repair abnormality, and other outcomes.