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EZH2 Blockade Reverses Doxorubicin Resistance by Disrupting Metabolic and DNA Repair Networks in Breast Cancer

ABSTRACT: Background: Doxorubicin (DOX) resistance remains a major obstacle to effective chemotherapy in breast cancer. However, the pharmacologically actionable regulators sustaining this resistant phenotype and its therapeutic vulnerabilities remain incompletely defined. Methods: DOX-resistant breast cancer cell models were established and treated with the EZH2 inhibitors tazemetostat or GSK126, alone or in combination with DOX. Cell viability, oxidative stress, DNA damage, and mitochondrial function were assessed in vitro. Transcriptomic profiling was performed to identify pathway alterations. A pH-responsive liposomal system for delivery of DOX and tazemetostat was developed and evaluated in vivo. Results: EZH2 was highly expressed in breast cancer and correlated with poor clinical outcomes. DOX treatment induced adaptive upregulation of EZH2 in both sensitive and resistant cells. Pharmacological inhibition of EZH2 markedly restored DOX sensitivity and exhibited strong synergistic cytotoxicity in resistant models. EZH2 blockade enhanced DOX-induced oxidative stress and DNA damage, with concomitant suppression of multiple DNA repair pathways and increased γH2AX accumulation. Transcriptomic and functional analyses revealed disrupted mitochondrial function and energy metabolism, characterized by loss of mitochondrial membrane potential and ATP depletion. In vivo, combined EZH2 inhibition and DOX significantly suppressed tumor growth, while pH-responsive liposomal delivery further enhanced antitumor efficacy and reduced systemic toxicity. Conclusion: EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Pharmacological targeting of EZH2 in combination with DOX represents a rational strategy to overcome chemoresistance in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327098 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:Resistance to tamoxifen is a major challenge in the treatment of estrogen receptor positive breast cancer. Acquired resistance to drug involves multilayered genetic and epigenetic regulation . The oncogene EZH2 plays significant role in the development of resistance against tamoxifen, widely used in the treatment of breast cancer. Inhibition of EZH2 has proven to reverse the tamoxifen resistance breast cancer cells back to the sensitive state. The molecular mechanism through which EZH2 inhibition triggers its effects are not known.This study was conducted to understand the global change in proteome profile of tamoxifen resistant MCF-7 breast cancer cells as a result of effect of EZH2 knockdown. Label Free Quantitative proteomics revealed a large number of proteins altered in acquired tamoxifen resistant cells compared to the sensitive cells. A total of 286 proteins were identified with normalized RT for each m/z out of which 86 proteins were upregulated by more than 1.3 fold and 98 proteins were down regulated by more than 1.3 fold in MCF-7 tamoxifen resistant breast cancer cells in comparison to the sensitive breast cancer cells. Upon EZH2 knockdown in tamoxifen resistant cells, a total of 115 proteins were found to be altered with 20 proteins upregulated by more than 1.3 fold and 49 proteins down regulated by more than 1.3 fold. Among the top upregulated proteins were L-lactate dehydrogenase A chain, Alpha and Gamma-enolase, Calreticulin, heat shock protein HSP-90-beta, Alpha-actinin-4, Elongation factor 1-alpha, Vimentin, Protein S100A6, Putative protein FAM10A5, Heterogeneous nuclear ribonucleoprotein A1 and Keratin 1. In addition, 15 proteins were found to be down regulated in EZH2si transfected tamoxifen sensitive cells which otherwise were highlyup regulated in resistant cells in the presence of normal level of EZH2. This indicates a possible regulation of these molecules by EZH2 leading to loss of resistance. Our data unveils important molecular players downstream to EZH2 knockdown leading to regain of sensitivity to tamoxifen in acquired tamoxifen resistance.Thus, EZH2 seems to exert its effects through regulation of metabolism, epithelial to mesenchymal transition and protein synthesis & folding. Hence, targeting EZH2 or the molecules down the cascade might be helpful in reacquiring sensitivity to tamoxifen intamoxifen-resistant cells.

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EZH2 Blockade Reverses Doxorubicin Resistance by Disrupting Metabolic and DNA Repair Networks in Breast Cancer

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