A Novel MLL5 Isoform That Is Essential to Activate <i>E6</i> and <i>E7</i> Transcription in HPV16/18-Associated Cervical Cancers

Yew, Chow Wenn; Lee, Pei; Chan, Wai Keong; Lim, Vania Kai Jun; Tay, Sun Kuie; Tan, Thiam Soon; Deng, Lih‐Wen

doi:10.1158/0008-5472.can-11-1271

Cited by 23 publications

(16 citation statements)

References 47 publications

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“…Yew et al previously identified an isoform of mixed lineage leukemia 5 (MLL5β), which regulates HPV E6/E7 oncogene transcription through its interaction with AP-1 at the 5′ segment of the HPV16/18 long control region (LCR) (29). Interestingly, Nin et al (30) reported that MLL5β was O-GlcNAcylated at T440 residue and this modification is necessary for its interaction with AP-1 and its recruitment to the HPV16/18-LCR.…”

Section: Discussionmentioning

confidence: 99%

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Zeng

Zhao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Two HR HPV genes, E6 and E7, are potent oncogenes based on their immortalizing and transforming activities in cell culture systems and their capacities to induce tumors in animal models. The HR HPV E7 oncoprotein binds to more than 20 cellular targets and interferes with multiple cellular processes, leading to deregulated cell cycle, centrosome amplification, DNA damage, anoikis resistance, anchorage-independent cell growth and malignant transformation as well as immune surveillance evasion.

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Section: Discussionmentioning

confidence: 99%

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Zeng

Zhao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…34 To date, several other isoforms listed in supplemental Table 3 have been reported besides MLL5. 35,36 Strikingly, compared with the other isoforms, NKp44L is characterized by a specific exon (21spe) at the C-terminus, probably implicated in its unique subcellular localization, as compared with the other MLL proteins. Importantly, the mRNA expression profiles of MLL5 and NKp44L are very different, pleotropic for MLL5, but significantly more restrictive to tumor cells for NKp44L.…”

Section: Discussionmentioning

confidence: 99%

Identification of a cellular ligand for the natural cytotoxicity receptor NKp44

Baychelier

Sennepin

Ermonval

et al. 2013

Blood

147

133

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Key Points• The cellular ligand of the NKp44L is a novel isoform of the mixed-lineage leukemia-5 protein.• NKp44L is not expressed on healthy cells, but on tumor and transformed cells, rendering them more sensitive for the NK cytotoxicity.With an array of activating and inhibitory receptors, natural killer (NK) cells are involved in the eradication of infected, transformed, and tumor cells. NKp44 is a member of the natural cytotoxicity receptor family, which is exclusively expressed on activated NK cells. Here, we identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. The sharply decreased NK lysis activity induced by anti-NKp44L antibodies directly demonstrates the role of NKp44L in cytotoxicity. Taken together, these results show that NKp44L could be critical for NK cellmediated innate immunity. The identification and cellular distribution of NKp44L highlight the role of this self-molecule as a danger signal to alert the NK cell network. (Blood. 2013; 122(17):2935-2942

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“…We have previously identified a novel MLL5 isoform, MLL5b, which was found to activate E6/E7 expression in HPV16/18-positive cells through the distal AP-1 site in the LCR (33). Knocking down MLL5b via a siRNA-duplex designed specifically to target only the isoform, downregulated E6 and E7, at both transcript and protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that MLL5b is essential in the activation of both the E6 and E7 transcription in HPV16/18-positive cells (33). With these observations, we hypothesized that the more pronounced antitumor effects of MLL5b-targeted silencing in HeLa cells was due to the combined effects of both apoptosis and senescence as a consequence of the downregulation of both E6 and E7 transcript levels.…”

Section: Targeted Silencing Of Mll5b Reduces the Colonyforming Abilitmentioning

confidence: 90%

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Targeted Silencing of MLL5β Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers

Nin¹,

Yew²,

Tay³

et al. 2014

Molecular Cancer Therapeutics

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We previously identified a novel MLL5 isoform, MLL5b, which was essential for E6 and E7 transcriptional activation in HPV16/18-associated cervical cancers. In this report, we investigated the potential of RNAimediated silencing of MLL5b through the use of MLL5b-siRNA as a novel therapeutic strategy for HPV16/18-positive cervical cancer. We observed concurrent downregulation of E6 and E7 after MLL5b 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 MLL5b-siRNA compared with E6-or E7-siRNA single treatments. Significant reduction in tumor size after MLLb-siRNA treatment in the HeLa xenograft tumor model further emphasized the importance of MLL5b in HPV16/18-associated tumor growth and the potential of RNAi therapeutics that target MLL5b. We also identified MLL5b as a modulator of gamma-irradiation (IR) sensitization properties of cisplatin. We observed that while MLL5b silencing alone was enough to evoke cisplatin-like IR sensitization in tumor cells in vitro, overexpression of MLL5b inhibited the ability of cisplatin to sensitize HeLa cells to IR-induced cytotoxicity. MLL5b-siRNA-IR cotreatment was also observed to enhance tumor growth inhibition in vivo. Taken together, our findings highlight the potential of targeted silencing of MLL5b via the use of MLL5b-siRNA as a novel therapeutic strategy and propose that MLL5b-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); 2572-82. Ó2014 AACR.

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A Novel MLL5 Isoform That Is Essential to Activate E6 and E7 Transcription in HPV16/18-Associated Cervical Cancers

Cited by 23 publications

References 47 publications

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

Identification of a cellular ligand for the natural cytotoxicity receptor NKp44

Targeted Silencing of MLL5β Inhibits Tumor Growth and Promotes Gamma-Irradiation Sensitization in HPV16/18-Associated Cervical Cancers

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