Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization

Abstract

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.

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

“…Overexpression of ZMYND8 in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. And 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 [131].…”

The paradigm of drug resistance in cancer: an epigenetic perspective

“…Furthermore, the expression of Phase-III transporters such as ABCC6 and SLC22A3 is also modulated by alterations in DNA methylations [ 55 ]. Interestingly, in triple-negative breast cancer, the chromatin reader and tumor suppressor protein ZMYND8 promote the formation of a transcription repressor complex with KDM5C and EZH2 that increases the H3K27me3 mark on promoters of ABCB1, ABCC1, and ABCC2 drug efflux pumps, thereby repressing their expression [ 56 ]. These pieces of evidence indicate the ability of CSCs to promote drug resistance by epigenetic modifications of DNA and chromatin landscape for up-regulating drug efflux pump expression.…”

Functional Roles of Bromodomain Proteins in Cancer

“…In addition, the activation of ZMYND8 expression through the all-trans-retinoic acid (ATRA) has been shown to inhibit cancer cell proliferation [ 264 ]. ZMYND8 promotes genes associated with terminal differentiation in opposition to the maintenance of cancer stem cells [ 265 ]. This stemness characteristic of cancer cells is associated with the development of resistance to chemotherapies and relapse.…”

“…Overexpression of ZMYND8 was shown to re-sensitize cells to chemotherapy via the recruitment of the EZH2 methyltransferase and lysine demethylase KDM5C corepressors to the promoters of tumor oncogenes. This resulted in an altered chromatin state, enriched in the repressive transcription mark H3K27me3 [ 265 ]. However, recent reports have indicated that ZMYND8 may also play an oncogenic role.…”