Abstract 2430: Targeting estrogen-related receptor alpha using pyrrole-imidazole polyamide

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Estrogen-related receptor α (ERRα), an orphan nuclear receptor, is a prominent regulator of mitochondrial biogenesis and function. We previously showed that liver-specific PTEN deletion and the subsequent activation of PI3K/AKT pathway lead to tumorigenesis. Here we show that Pten-null hepatocytes established from Pten-null mice exhibit dramatically increased ERRα expression, accompanied by elevated mitochondrial mass, cellular oxygen consumption and reactive oxygen species production. Silencing ERRα by siRNA in Pten-null hepatocytes not only suppresses mitochondrial biogenesis and respiration but also attenuates hepatocytes' proliferation and colony-forming potential. Cohort analyses of clinical datasets from liver tissues revealed a negative correlation between expressions of PTEN and ERRα in patients with liver cancer. Therefore, targeting ERRα might provide therapeutic implication for treating tumors bearing abnormal PTEN-ERRα signaling. ERRα exerts transcriptional activity towards its target genes via binding to consensus DNA sequences named estrogen-related receptor α response elements (ERRE). The DNA-binding activity of ERRα could be modulated by polyamides, a class of synthetic amino acid oligomers capable of binding to DNA minor groove with sequence specificity. By designing and employing polyamide that specifically targets ERRE in Pten-null hepatocytes, we found the mRNA levels of two ERRα target genes, cytochrome c (cyt c) and ATP synthase β (ATP5b), are reduced. Biochemical gel-shift assay showed the binding between ERRα and ERRE is significantly diminished by polyamides in vitro. Moreover, polyamide treatment in hepatocytes reduced mitochondrial respiration and colony-forming ability. In conclusion, our findings show that ERRα is significantly induced via PTEN-AKT signaling pathway and in turn activates mitochondrial bioenergetics, which likely provides growth and survival advantages. The crucial role in mitochondrial metabolism and the association with PTEN signaling make ERRα a useful target for cancer therapy. Synthetic polyamide that disrupts transcription factor-DNA interaction can be utilized to modulate ERRα's activity, highlighting its potential as a future therapeutic target. Citation Format: Yang Li, John Gallagher, Bogdan Olenyuk, Bangyan Stiles, Ankeste Kassa. Targeting estrogen-related receptor alpha using pyrrole-imidazole polyamide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2430. doi:10.1158/1538-7445.AM2014-2430