A Heme-Binding Transcription Factor BACH1 Regulates Lactate Catabolism Suggesting a Combined Therapy for Triple-Negative Breast Cancer.
Joselyn PadillaBok-Soon LeeKaren ZhaiBethany RentzTia BoboNorca Maritza DowlingJiyoung LeePublished in: Cells (2022)
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.
Keyphrases
- transcription factor
- induced apoptosis
- cell cycle arrest
- signaling pathway
- oxidative stress
- poor prognosis
- endoplasmic reticulum stress
- machine learning
- risk assessment
- drug delivery
- long non coding rna
- big data
- electronic health record
- young adults
- pi k akt
- lymph node metastasis
- cancer therapy
- artificial intelligence
- heat stress
- data analysis