Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization

• Published in: Cell death & disease Vol. 11; no. 12; pp. 1073 - 18
• Main Authors: Mukherjee, Shravanti, Adhikary, Santanu, Gadad, Shrikanth S., Mondal, Payel, Sen, Sabyasachi, Choudhari, Ramesh, Singh, Vipin, Adhikari, Swagata, Mandal, Pratiti, Chaudhuri, Soumi, Sengupta, Amrita, Lakshmanaswamy, Rajkumar, Chakrabarti, Partha, Roy, Siddhartha, Das, Chandrima
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.12.2020; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/39; 38/43; 38/90; 42/109; 45; 45/29; 631/337/176/2016; 631/67/1347; 64; 64/60; Animals; Antibodies; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast carcinoma; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Chemotherapy; Chromatin; Down-Regulation - drug effects; Down-Regulation - genetics; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic - drug effects; Epigenetics; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genome, Human; Histone Demethylases - metabolism; Humans; Immunology; Invasiveness; Life Sciences; Medical prognosis; Metastases; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncogenes; Phenotype; Phenotypes; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Suppressor Proteins - metabolism; Zinc finger proteins
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03129-x

The major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.