Abstract 370: BACH1 metastatic activity is regulated by oxygen-dependent proline hydroxylation in triple-negative breast cancer

Abstract

Abstract Hypoxia, low oxygen availability at the tissue level, is a key driver of metastasis in solid tumors. Oxygen-sensitive activation of hypoxia-induced transcription factors is in part regulated by prolyl hydroxylase domain proteins (PHDs). We and others previously showed that the BTB and CNC homolog 1 (BACH1) transcription factor promotes metastasis in various cancer types. In accompanying work, we show that BACH1 is prolyl-hydroxylated and degraded in an oxygen-dependent manner in triple-negative breast cancer (TNBC). Here we show that BACH1 lacking its hydroxylated proline sites (i.e., mutant BACH1) expressed in TNBC cells exhibits increased DNA binding to a canonical BACH1 binding site as well as greater transcriptional output of metastasis and hypoxia-response-related genes relative to wild-type BACH1. Furthermore, in vivo assays showed that mutant BACH1 promotes greater tumor metastasis of TNBC cells than wild-type BACH1. Our findings suggest that the proline hydroxylation of BACH1 directly regulates BACH1’s transcriptional activity by modulating its DNA-binding activity. Together, these results reveal a mechanism underlying oxygen-sensitive regulation of BACH1 that could potentially contribute to BACH1-mediated pro-metastatic signaling and therapeutic resistance under hypoxia in TNBC. Citation Format: Thomas Li, Long Chi Nguyen, Christopher Dann, Madeline Henn, Dongbo Yang, Emily Shi, Lydia Robinson-Mailman, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 metastatic activity is regulated by oxygen-dependent proline hydroxylation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 370.