cGAS/STING-Independent Induction of Type I Interferon by Inhibitors of the Histone Methylase KDM5B

Studies support the role of hexamethylene bis-acetamide [HMBA] induced protein 1 (HEXIM1) as a tumor suppressor. We previously reported that the histone demethylase, KDM5B, inhibits the expression of HEXIM1, and KDM5B inhibitors (KDM5Bi) upregulate HEXIM1 expression. As a consequence, KDM5Bi inhibited cell proliferation, induced differentiation, potentiated sensitivity to cancer chemotherapy, and inhibited breast tumor metastasis. HEXIM1 is crucial for the regulation of triple-negative breast cancer (TNBC) phenotype by KDM5Bi. Type I Interferon (IFN-I) employs the immune system in the tumor microenvironment to restrict tumor growth. Moreover, therapeutic approaches (including mainstay chemotherapy) engage IFN-I signaling. We report herein that HEXIM1 and KDM5Bi induce IFN-I in TNBC. HEXIM1 and KDM5Bi downregulate the expression of polyribonucleotide nucleotidyltransferase 1 (PNPT1) resulting in the release of mitochondrial dsRNA (mt-dsRNA) into the cytoplasm. HEXIM1 also upregulates melanoma differentiation-associated protein 5 (MDA5), a cytoplasmic viral RNA receptor in the innate immune system. MDA5 is required for HEXIM1 and KDM5Bi to induce IFN-I and downstream signaling factors. We observed the augmentation of DNA damage response to Doxorubicin in the presence of KDM5Bi, and this action is a contributing factor in KDM5Bi-induced IFN-I. These actions of HEXIM1 and KDM5Bi occur independently of Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (cGAS/STING), a major DNA sensing pathway and inducer of innate immunity. Via the upregulation of HEXIM1, KDM5Bi represent pharmacologically induced and tumor intrinsic IFN-I production that is cGAS/STING independent. This is critical because cGAS/STING induce an inflammatory response that promotes the survival of cancer cells, and STING is often impaired in malignant cancers.