Abstract
BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.
Highlights
Metabolism is an essential process to acquire necessary nutrients from outside of cells and utilize them into biomass to maintain cell viability
Transient silencing of COX15 or UQCRC1 using siRNA in the brac-Tramtrack-Broad complex (BTB) domain and Cap ‘n’ Collar (CNC) homology 1 (BACH1)-depleted cells as low as the levels of those in control cells completely restored metformin resistance and rescued cell growth. These results indicate that mitochondrial oxidative phosphorylation (OXPHOS) plays a critical role for metformin resistance in triple-negative breast cancer (TNBC) cells and is altered by BACH1 manipulation
Preclinical studies and bioinformatic approaches suggest that breast tumors expressing low levels of BACH1 might be potentially sensitive to metformin treatment, while those enriched with BACH1 might be resistant to metformin treatment when administered as a single agent to manage tumors [10]
Summary
Metabolism is an essential process to acquire necessary nutrients from outside of cells and utilize them into biomass to maintain cell viability. Two BACH family protein members, BACH1 and BACH2, have homologous sequences and structures containing a BTB and the bZIP domain, heme-binding motifs, and the cytoplasmic localization signal (CLS) [17] Both BACH1 and BACH2 are widely expressed in most human tissues. BACH1 is released from the DNA and undergoes nuclear export for ubiquitin-dependent degradation, releasing transcription suppression of the BACH1 target gene, heme oxygenase 1 (HMOX1 or HO-1) [23,24]. Exogeneous porphyrin treatment treatment reduces BACH1 levels, modifying metastasis and metabolic programs of cancer cells. Reduces BACH1 levels, modifying metastasis and metabolic programs of cancer cells. For the post-transcriptional gene expression regulation, let-7 miRNA is known to suppress BACH1 levels by interacting with the 30 untranslated region (UTR) of BACH1 in breast cancer cells and hepatocytes, [26,28,29]. Hypoxia is known to induce BACH1 transcripts, it is unclear whether BACH1 mRNA induction is mediated by HIFs [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
