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. 2024 Jun:170:156-169.
doi: 10.1016/j.molimm.2024.04.012. Epub 2024 Apr 30.

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

Ian MacFawn  1 , Joshua Farris  2 , Phillip Pifer  3 , Naira V Margaryan  4 , Halima Akhter  5 , Lei Wang  5 , Sebastian Dziadowicz  5 , James Denvir  6 , Gangqing Hu  7 , Steven M Frisch  8
Affiliations

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

Ian MacFawn et al. Mol Immunol. 2024 Jun.

Abstract

Type-I and -III interferons play a central role in immune rejection of pathogens and tumors, thus promoting immunogenicity and suppressing tumor recurrence. Double strand RNA is an important ligand that stimulates tumor immunity via interferon responses. 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, using genomics and signaling approaches, we show that Grainyhead-like-2 (GRHL2), a master programmer of epithelial cell identity, promotes type-I and -III interferon responses to double-strand RNA. GRHL2 enhanced the activation of IRF3 and relA/NF-kB and the expression of IRF1; a functional GRHL2 binding site in the IFNL1 promoter was also identified. Moreover, 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.

Keywords: Epithelial-mesenchymal transition; Grainyhead-like-2; IRF-3; Interferon; Tumor recurrence.

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Conflict of interest statement

Declaration of Competing Interest No conflicts of interest are reported.

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