A plethora of chemotherapeutic drugs like anthracyclines (such as doxorubicin and epirubicin), taxanes (paclitaxel and docetaxel), 5-Fluorouracil and cyclophosphamide are effective in eliminating breast cancer in pre-clinical studies, but their clinical efficacy is mostly limited due to their toxic side-effects. The efficiency of these drugs are further constrained in highly invasive and therapy-resistant subtype, triple negative breast cancer (TNBC). It is often found that patients are intolerant to the effective tumor elimination dose of chemotherapeutic drug, while the levels that can be tolerated are therapeutically insufficient. This low dose leads to acquisition of resistant properties and thus secondary metastasis. Therefore, this shortcoming of chemotherapy could be compensated using specific therapeutic agents which primes the cells more prone to chemotherapy, a phenomenon termed as chemo-sensitization. Recently, it has been established ZMYND8 is a potent tumor suppressor in various malignancies including breast cancer. We found ZMYND8 suppresses stemness, drug resistance and tumor promoting genes. Low dose of chemotherapeutic drugs like doxorubicin or 5-flurouracil promotes tumorigenicity. Interestingly, we found reinstating ZMYND8, chemo sensitizes and suppresses doxorubicin induced tumor phenotypes in vivo. Quick activation of a plethora of genes takes place upon different environmental cues like drug treatment. These genes are endowed with ‘poised’ epigenetic states, a characteristic feature of embryonic stem cell. Poised promoters are generally characterized by the co-existence of both repressive mark (H3K27me3/H3K9me3) and  activating (H3K4me3) epigenetic marks. Limited studies have been implied the existence of bivalent genes in cancer. Our study showed ZMYND8 represses these poised oncogenes, upon low dose of drug treatment, through its interaction with KDM5C and EZH2. Thus, ZMYND8 represses poised oncogenes through its association with epigenetic repressors in chemo-refractory breast carcinoma.

Poised for chemo-resistance: suppression of poised oncogenes by ZMYND8, triggers chemo-sensitization

ACS Spring Meeting 2021

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