Accumulating evidences indicate the involvement of epigenetic deregulations in cancer. While some epigenetic regulators with aberrant functions in cancer are targeted for improving therapeutic outcome in patients, reinstating the functions of tumor-suppressor-like epigenetic regulators might further potentiate anti-cancer therapies. Epigenetic reader zinc-finger MYND-type-containing 8 (ZMYND8) has been found to be endowed with multiple anti-cancer functions like inhibition of tumor cell migration and proliferation. Here, we report another novel tumor suppressor role of ZMYND8 as an inducer of differentiation in breast cancer cells, by upregulating differentiation genes. Interestingly, we also demonstrated that ZMYND8 mediates all its anti-tumor roles through a common dual-histone mark binding to H4K16Ac and H3K36Me2. We validated these findings by both biochemical and biophysical analyses. Furthermore, we also confirmed the differentiation-inducing potential of ZMYND8 in vivo, using 4T1 murine breast cancer model in Balb/c mice. Differentiation therapy holds great promise in cancer therapy, since it is non-toxic and makes the cancer cells therapy-sensitive. In this scenario, we propose epigenetic reader ZMYND8 as a potential therapeutic candidate for differentiation therapy in breast cancer.
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This work was funded by research grants from Biomolecular Assembly, Recognition and Dynamics Project (Grant 12-R&D-SIN-5.04-0103) from the Department of Atomic Energy, India, and Science and Engineering Research Board File No. EMR/2014/000335 by Department of Science and Technology (DST), India, provided to CD. SM, SA, AS and PM thank SERB-NPDF, CSIR, DBT-RA programme and DST, India, respectively for fellowship support. We also thank the Genome Informatics Research and Development Unit, Bionivid Technology Pvt. Ltd., for help in microarray data analysis.
This article is part of the Topical Collection: Chromatin Biology and Epigenetics.
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Mukherjee, S., Sen, S., Adhikary, S. et al. A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dual-histone binding function. J Biosci 45, 2 (2020). https://doi.org/10.1007/s12038-019-9980-5
- dual-histone reader