Abstract
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.
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Acknowledgements
This work was funded by the National Natural Science Foundation of China grants 31770863 to YLC, 81973316 to JHH, and 81803517 to XXY.
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Conceptualization: YLC and JHH; methodology and investigation: XYH, MMZ, JZ, CYW, XKZ, SZ, XXY, and YJD; software: XYH and BTZ; clinical sample collection: DCZ; writing—original draft preparation: XYH and MMZ; writing—review and editing: YLC; supervision: YLC; funding acquisition: YLC, XXY, and JHH. All authors have read and agreed to the final version of the manuscript.
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He, Xy., Zhu, Mm., Zheng, J. et al. Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression. Acta Pharmacol Sin 44, 635–646 (2023). https://doi.org/10.1038/s41401-022-00961-z
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DOI: https://doi.org/10.1038/s41401-022-00961-z
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