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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling


Moon EJEui Jung , Mello SSStephano S , Li CGCaiyun G , Chi JTJen-Tsan , Thakkar KKaushik , Kirkland JGJacob G , Lagory ELEdward L , Lee IJIk Jae , Diep ANAnh N , Miao YYu , Rafat MMarjan , Vilalta MMarta , Castellini LLaura , Krieg AJAdam J , Graves EEEdward E , Attardi LDLaura D , Giaccia AJAmato J . Nature communications. 2021 7 14; 12(1). 4308


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.