Document Type
Article
Publication Date
5-12-2025
Abstract
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.
Keywords
breast cancer, cancer therapy, histone demethylase, interferon, mitochondria
Language
English
Publication Title
FASEB Journal
Rights
© 2025 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/), which permits non-commercial copying and redistribution of the material in any medium or format, provided the original work is not changed in any way and is properly cited.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Montano, M.M., Yeh, I.-J. and Ketchart, W. (2025), cGAS/STING-Independent Induction of Type I Interferon by Inhibitors of the Histone Methylase KDM5B. The FASEB Journal, 39: e70629. https://doi.org/10.1096/fj.202500628R
Manuscript Version
Final Publisher Version