Abstract 1433: Estrogen-related receptor alpha (ERRα) functions to promote prostate cancer cell stemness via its transcriptional regulation of ZIP1 and ACON2 to enhance oxidative phosphorylation

Accumulating evidences suggest that cancer stem-like cells (CSCs) play critical roles in cancer relapse and metastasis, likely due to their strong self-renewal capacity and chemo-radiotherapy resistance. Recent advances also indicate that the energy metabolism status of the CSCs differs greatly from the bulk cancer cells, and that such energy metabolism shift may favor the maintenance of cancer cell stemness. Estrogen-related receptor alpha (ERRα, NR3B1) is a key energy metabolism regulator. In this study, we aim to characterize its role in the energy metabolism regulation in prostate cancer stem-like cells (PCSCs). By analyzing the oxygen consumption and extracellular acidification rates using the Seahorse XF Analyzer, we revealed that the PCSCs, isolated from prostate cancer cell lines (LNCaP, DU145 and PC3) by low attachment 3D-culture, exhibited lower aerobic glycolysis but higher oxidative phosphorylation status. Expression analyses by qPCR and Western blot showed that the isolated PCSCs expressed higher levels of ERRα. Further functional studies showed that overexpression of ERRα could promote the oxidative phosphorylation but lower the glycolysis status, and also enhance the 3-D spheroid formation capacity (stemness) of prostate cancer cells (LNCaP, DU145 and PC3), whereas its knockdown could reverse the effects. Furthermore, we identified by combined chromatin immunoprecipitation (ChIP) and PCR analysis that ERRα could directly regulate two key energy metabolic genes ACON2 (a rate limiting enzyme in TCA cycle) and ZIP1 (a zinc transporter) in PCSCs. Western blot analysis showed that ERRα could up-regulate the ACON2 but repress the ZIP1 expression, whereas its knockdown reverse the expressions of these two proteins in prostate cancer cells. Together, our results show that ERRα can promote the stemness of prostate cancer cells and enhance the cellular energy metabolism towards oxidative phosphorylation in PCSCs via its transcriptional regulation of ACON2 and ZIP1 genes.This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107116). Citation Format: Taiyang Ma, Zhenyu Xu, Yuliang Wang, Zhu Wang, Weijie Gao, Wenxin You, Leung Franky Chan. Estrogen-related receptor alpha (ERRα) functions to promote prostate cancer cell stemness via its transcriptional regulation of ZIP1 and ACON2 to enhance oxidative phosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1433.