Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence [ATAC-seq]

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Differentiation of embryonic stem cells to pluripotent epithelial cells activates the interferon response during development, raising the question of whether epithelial vs. mesenchymal gene signatures in cancer potentially regulate the interferon pathway as well. Here we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes the type-I and -III interferon responses to double-strand RNA, an important ligand for immune rejection of tumors via interferons. The positive effects of GRHL2 were mediated by enhanced IRF3 and relA/NF-kB activation, upregulation of IRF1, and a functional GRHL2 binding site identified in the IFNL1 promoter. In addition, time to recurrence in breast cancer correlated positively with GRHL2 protein expression, indicating that GRHL2 is a tumor recurrence suppressor, consistent with its enhancement of interferon responses. These observations demonstrate that epithelial cell identity supports interferon responses in the context of cancer.