Abstract
Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.
Highlights
Hypoxia plays a critical role in tumor progression including invasion and metastasis
Using Gene Expression Omnibus (GEO) dataset (GSE19783), we found that the combined expression of these genes correlated with poor patient survival, suggesting an oncogenic role for them in breast cancer (Fig. 1b)
We found that three genes (MAFF, LOX, AKAP12) significantly regulate cell invasion without having an effect on cell death when they were knocked down both under normoxia and hypoxia
Summary
Hypoxia plays a critical role in tumor progression including invasion and metastasis. HIFα forms a heterodimer with HIFβ and binds to hypoxia response elements (HREs), resulting in transactivation of downstream genes that promote tumor progression[4,5]. We identified hypoxia-induced v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a HIF-1 target gene, which is regulated by hypoxia. While CNC family members including NRF2 positively transactivate target genes involved in antioxidative responses, BACH1 and BACH2, or homodimers of small MAF proteins can play a repressive role in regulating MARE and AREdependent genes by competing with NF-E2 and NRF2 for MARE or ARE binding[10,11]. We demonstrate that MAFF, which is induced by HIF-1 under hypoxia, binds with BACH1 and promotes tumor invasion and metastasis by transcriptionally activating IL11 and promoting STAT3 pathways
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