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

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Authors: Eui Jung Moon ; Stephano S Mello ; Caiyun G Li ; Jen-Tsan Chi ; Kaushik Thakkar ; Jacob G Kirkland ; Edward L Lagory ; Ik Jae Lee ; Anh N Diep ; Yu Miao ; Marjan Rafat ; Marta Vilalta ; Laura Castellini ; Adam J Krieg ; Edward E Graves ; Laura D Attardi ; Amato J Giaccia

MeSH: Animals ; Basic-Leucine Zipper Transcription Factors / metabolism ; Breast Neoplasms / genetics ; Breast Neoplasms / metabolism ; Breast Neoplasms / mortality ; Breast Neoplasms / pathology* ; Cell Hypoxia ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* ; Interleukin-11 / metabolism* ; MafF Transcription Factor / genetics ; MafF Transcription Factor / metabolism* ; Mice ; Neoplasm Invasiveness / pathology ; Neoplasm Metastasis / pathology ; Nuclear Proteins / genetics ; Nuclear Proteins / metabolism* ; Prognosis ; STAT3 Transcription Factor / metabolism* ; Signal Transduction ; Transcription, Genetic

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.