Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression

Xiao-yu He1, Meng-meng Zhu1, Juan Zheng1, Cheng-yi Wang1, Xiao-kang Zhao1, Bao-tong Zhang2, Da-chen Zhou3, Shuang Zhang1, Xiao-xiao Yang1, Ya-jun Duan1, Ji-hong Han4, Yuan-li Chen1
1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
2 Department of Human Cell Biology and Genetics, Southern University of Science and Technology, School of Medicine, Shenzhen 518055, China
3 Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
4 College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Correspondence to: Ji-hong Han:, Yuan-li Chen:,
DOI: 10.1038/s41401-022-00961-z
Received: 2 March 2022
Accepted: 13 July 2022
Advance online: 22 August 2022


Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1−0.5 μM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might
be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.
Keywords: HCC; LXR; REPS2; EGFR; endocytosis; T0901317

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