Abstract 357: Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated breast cancer

Approximately 3.6% human cancers worldwide derive from chronic alcohol drinking, including cancers of breast and multiple other organs. Alcohol intake is consistently associated with an increased risk of BC (breast cancer). Alcohol consumption is more pronounced in ER+ BC cases than in ER- cases. However, the molecular mechanism remains to be determined. RNA polymerase (Pol) III genes, such as 5S rRNA and tRNAs, are elevated in both transformed and tumor cells. Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB complex, specifically regulates Pol III gene transcription. Our studies have demonstrated that Brf1 expression and Pol III gene transcription are increased in alcohol-induced mice liver tumor. Alcohol-induced deregulation of Pol III gene transcription may be fundamental to the development of BC. We have found that alcohol-increased Pol III gene transcription in ER+ BC cells is significantly higher than in ER- normal breast cells and BC cells. The induction is ER dependent. The cellular levels of Brf1 protein and mRNA are increased in ethanol-treated MCF-7 cells. Ethanol markedly stimulates phosphorylation of MSK1 (MSK1ph) and histone H3 (H3ph). Our previous studies demonstrated that MSK1 mediates H3ph. MSK1 mediates ERα expression. Inhibition of MSK1 signal reduces alcohol-induced ERα expression to decrease cellular level of Brf1 and Pol III genes. Repression of Brf1 expression decreases alcohol-induced anchorage-independent cell growth and tumor formation. Furthermore, our analysis indicates that ethanol treatment increases occupancy of ERα to Brf1 promoter. The results by using Co-IP and ChIP assays indicate that MSK1, ERα and Brf1 form a complex to mediate Pol III gene transcription. Studies of human biopsies of BC patients indicate that Brf1 expression is increased in human cases of BC. High expression of Brf1 displays longer overall survival period after Tamoxifen treatment. Co-localization analysis indicate that MSK1ph and H3S10ph localizes in nuclear with Brf1. These results support the idea that alcohol activates MSK1 and induces epigenetic modification of H3ph to enhance ERα and Brf1 expression and Pol III gene transcription, resulting greater phenotypic changes. Together, our studies indicate that ethanol-induced epigenetic modification of H3ph may play a critical role in alcohol-induced cell transformation and alcohol-associated ER+ BC. The project is supported by NIH grants: AA017288, AA021114, AA02324 and AA024169 Citation Format: Lei Lu, Zeng Fang, Wen Li, Zhimin He, Shuping Zhong. Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated breast cancer [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 357.