RGD Reference Report - Targeted Silencing of MLL5beta Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers. - Rat Genome Database

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Targeted Silencing of MLL5beta Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers.

Authors: Nin, DS  Yew, CW  Tay, SK  Deng, LW 
Citation: Nin DS, etal., Mol Cancer Ther. 2014 Aug 29.
RGD ID: 9588553
Pubmed: PMID:25172963   (View Abstract at PubMed)
DOI: DOI:10.1158/1535-7163.MCT-14-0019   (Journal Full-text)

We previously identified a novel MLL5 isoform, MLL5beta, 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 MLL5beta through the use of MLL5beta-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5beta 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 MLL5beta-siRNA compared with E6- or E7-siRNA single treatments. Significant reduction in tumor size after MLLbeta-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5beta in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5beta. We also identified MLL5beta as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5beta silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5beta inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5beta-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5beta via the use of MLL5beta-siRNA as a novel therapeutic strategy and propose that MLL5beta-siRNA could be a viable alternative for cisplatin in the current cisplatin-based chemotherapeutics for HPV16/18-associated cervical cancers. Mol Cancer Ther; 13(11); 1-11. (c)2014 AACR.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cervical cancer  IMP 9588553human gene in a mouse modelRGD 
cervical cancer  ISOKMT2E (Homo sapiens)9588553; 9588553human gene in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Kmt2e  (lysine methyltransferase 2E)

Genes (Mus musculus)
Kmt2e  (lysine (K)-specific methyltransferase 2E)

Genes (Homo sapiens)
KMT2E  (lysine methyltransferase 2E (inactive))


Additional Information