Abstract B52: HIF-ZMYND8-BRD4 axis mediates breast cancer progression and metastasis

Abstract

Abstract Metastatic breast cancer is lethal and incurable. The major obstacle to ending this aggressive disease is the absence of definitive prognostic biomarker and effective therapeutic target. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, how epigenetic dysregulation under tumor hypoxia stimulates breast cancer progression and metastasis remains unknown. We recently identified the epigenetic reader ZMYND8 as a novel HIF target gene by analyzing expression changes of 720 epigenetic genes in three microarray gene expression and mRNA sequencing datasets. Analysis of a human breast cancer tissue microarray revealed that ZMYND8 is highly expressed in invasive breast tumors and high levels of ZMYND8 are significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion significantly suppresses colony formation, invasion, and migration of breast cancer cells in vitro, and inhibits breast tumor growth and metastasis in mice. To figure out the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation, and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia response elements (HREs) to stimulate the expression of HIF target genes LOX, AGR2, AQP1, and VEGFA. HIF is required for ZMYND8-mediated breast cancer growth and metastasis in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with the bromodomains of BRD4 and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation and subsequent transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, these findings indicate that p300-acetylated ZMYND8 mediates breast cancer progression and metastasis by BRD4-dependent activation of HIF. In summary, ZMYND8 represents a positive-feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and may be a potential epigenetic target for the prognosis and treatment of breast cancer. Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. HIF-ZMYND8-BRD4 axis mediates breast cancer progression and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B52.