Abstract 386: BACH1 is a key regulator of the tumor hypoxia response

Abstract Hypoxia is an important hallmark of aggressive solid tumors and a key driver of metastasis and resistance to therapy. Hypoxic stress induces the activation of various factors, such as hypoxia-inducible factors (HIFs), which facilitate cellular adaptation and promote tumorigenesis. Given the complexity of this mechanism, identifying novel targets that sensitize hypoxic tumors to therapy could have significant clinical impact. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase (PHD), similar to HIFs, in an oxygen-dependent manner. We describe two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increases protein turnover and decreases DNA binding in normoxia. We further demonstrate HIF-independent induction of BACH1 within multiple TNBC (Triple-Negative Breast Cancer) cell lines and patient-derived organoids under hypoxic conditions. Utilizing ChIP-seq, bulk, single-cell and spatial transcriptomics across diverse BACH1 knockout tumor models, our study revealed that BACH1 selectively and directly modulates the transcriptional response associated with hypoxia and stress in TNBC. Our findings identify BACH1 as 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, Madeline Henn, Emily Shi, Thomas Li, Letícia Stock, Wenchao Liu, Margarite Matossian, Andrea Valdespino, Yoo Jane Han, Jing Zhang, Geetha Priyanka Yerradoddi, Yan Li, Mitsuyo Matsumoto, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 is a key regulator of the tumor hypoxia response 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 (6Suppl): Abstract nr 386.