A Heme-Binding Transcription Factor BACH1 Regulates Lactate Catabolism Suggesting a Combined Therapy for Triple-Negative Breast Cancer

Authors

Joselyn Padilla, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, Washington, DC 20037, USA.
Bok-Soon Lee, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, Washington, DC 20037, USA.
Karen Zhai, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, Washington, DC 20037, USA.
Bethany Rentz, Animal Research, Office of the Vice Provost for Research, 1922 F Street NW, Washington, DC 20052, USA.
Tia Bobo, Animal Research, Office of the Vice Provost for Research, 1922 F Street NW, Washington, DC 20052, USA.
Norca Maritza Dowling, Department of Acute & Chronic Care, School of Nursing, Washington, DC 20037, USA.
Jiyoung Lee, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, Washington, DC 20037, USA.

Document Type

Journal Article

Publication Date

3-31-2022

Journal

Cells

Volume

11

Issue

7

DOI

10.3390/cells11071177

Keywords

BACH1; lactate catabolism; lactate transporter; novel combination therapy targeting BACH1 and MCT1; triple-negative breast cancer

Abstract

The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.

APA Citation

Padilla, Joselyn; Lee, Bok-Soon; Zhai, Karen; Rentz, Bethany; Bobo, Tia; Dowling, Norca Maritza; and Lee, Jiyoung, "A Heme-Binding Transcription Factor BACH1 Regulates Lactate Catabolism Suggesting a Combined Therapy for Triple-Negative Breast Cancer" (2022). GW Authored Works. Paper 512.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/512

Department

Biochemistry and Molecular Medicine