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Molecular cancer therapeutics

Targeted silencing of MLL5β inhibits tumor growth and promotes gamma-irradiation sensitization in HPV16/18-associated cervical cancers.


PMID 25172963

Abstract

We previously identified a novel MLL5 isoform, MLL5β, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAi-mediated silencing of MLL5β through the use of MLL5β-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5β silencing, leading to growth inhibition via the activation of apoptosis and senescence in the HeLa cell model. This corresponded with the enhanced antitumor effects of MLL5β-siRNA compared with E6- or E7-siRNA single treatments. Significant reduction in tumor size after MLLβ-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5β in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5β. We also identified MLL5β as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5β silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5β inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5β-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5β via the use of MLL5β-siRNA as a novel therapeutic strategy and propose that MLL5β-siRNA could be a viable alternative for cisplatin in the current cisplatin-based chemotherapeutics for HPV16/18-associated cervical cancers.