The Therapeutic Effect of EZH2 Inhibitors in Targeting Human Papillomavirus Associated Cervical Cancer

High-risk human papillomavirus (HPV) is a crucial risk factor in the development of cervical cancer, where epigenetic modifications and epithelial-mesenchymal transition (EMT) processes have been implicated in cancer progression and metastasis. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is frequently overexpressed in HPV-associated cervical cancers and has been linked to tumour progression. However, there is still no consensus on the mechanisms of their action and their effectiveness on HPV-associated cancers. This study aimed to investigate whether EZH2 inhibitors (EPZ6438 and ZLD1039) can be effective in managing cervical cancer with less toxic effects than the conventional chemotherapeutic drug cisplatin. Proliferation assay and flow cytometry results showed that EZH2 inhibitors effectively induced apoptosis and arrested cells in G0/G1 phase in both HPV+ and HPV- cervical cancer cells. Both inhibitors downregulated the expression of EZH2 and HPV16 E6/E7 at mRNA and protein levels whilst upregulating expressions of p53 and Rb and epithelial markers. In summary, both EZH2 inhibitors showed therapeutic potential in comparison to cisplatin based on cellular and molecular readouts. Additionally, EPZ6438 showed a greater efficacy and higher sensitivity towards HPV+ cells, which was further supported by preliminary in vivo results from the chorioallantoic membrane assay.