BACH1 regulates the hypoxia response and metastasis in triple negative breast cancer

Abstract Hypoxia is an important hallmark of aggressive solid tumors. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase 1 (PHD1) in an oxygen-dependent manner. Using mass spectrometry, we identified two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increased protein turnover in normoxia. Notably, a clinically relevant BACH1 mutant (BACH1M) resistant to hydroxylation displays enhanced BACH1 DNA binding capacity. Triple-negative breast cancer (TNBC) cells expressing BACH1M showed higher invasion in vitro and increased metastasis in vivo. Loss of BACH1 reduced the cellular transcriptional hypoxic response. Under hypoxia, BACH1 increases chromatin accessibility and gene expression through chromatin remodeling involving direct BACH1 binding and indirect epigenetic regulation. These results indicate that hypoxia stabilizes and enhances the pro-metastatic transcriptional activity of BACH1 through loss of prolyl hydoxylation in TNBC. Our findings identify BACH1 as an oxygen sensitive effector of the hypoxia response and a clinically relevant target for attenuating hypoxia induced, pro-metastatic signaling and therapeutic resistance in cancers. Citation Format: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Emily Shi, Thomas Li, Joseph Wynne, Letícia Stock, Madeline Henn, Zeyu Qiao, Andrea Valdespino, Raven Watson, Wenchao Liu, Lydia Robinson-Mailman, Galina Khramtsova, Mitsuyo Matsumoto, Raymond Moellering, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 proline hydroxylation regulates the hypoxia response and metastasis in triple negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4807.