Abstract 5495: Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss

Abstract

Abstract Mitochondrial dysfunction has been attributed to be a major cause for fatty liver development and also underlies tumor development. Using a liver-conditional Pten deletion model where the activation of its downstream PI3K/AKT signaling led to fatty liver, steatohepatitis, fibrosis and finally liver cancer development, we reported previously that the fatty liver and liver cancer is accompanied by elevated mitochondrial bioenergetics and a dramatic induction of estrogen-related receptor α (ERRα), a master regulator that orchestrate mitochondria response to modulate metabolism. In this project, we intended to investigate whether blocking ERRα expression and inhibiting mitochondrial respiration can attenuate tumor growth and lipid accumulation in the Pten null livers and human liver cancer cells. Using a genetic knockdown approach with siERRα and chemical genomic approach with a small molecular polyamide compound that binds to the ERRα consensus binding site, we showed that ERRα knockdown suppressed mitochondrial function and impeded cell proliferation in human liver as well as prostate cancer cell lines lacking Pten. In addition, blocking ERRα transcriptional activity with ERRα specific polyamide err-PA significantly reduced tumor growth in xenograft models. Furthermore, err-PA administration in vivo in 1.5-month old liver- specific Pten null mice remarkably prevented the development of fatty liver morphology and quantitatively reduced the hepatic triglyceride level. In summary, our study highlights ERRα's crucial role in regulating mitochondrial bioenergetics and underscores its therapeutic potential in cancer and lipid disorders. Citation Format: Chien-Yu Chen, Yang Li, Jingyu Chen, Lina He, Bangyan Stiles. Inhibiting ERRα blocks liver steatosis and tumorigenesis induced by PTEN loss [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 5495.