The Hippo/
            <scp>YAP</scp>
            pathway interacts with
            <scp>EGFR</scp>
            signaling and
            <scp>HPV</scp>
            oncoproteins to regulate cervical cancer progression

He, Chunbo; Mao, Dagan; Hua, Guohua; Lv, Xiaozhen; Chen, Xingcheng; Angeletti, Peter C.; Dong, Jixin; Remmenga, Steven W.; Rodabaugh, Kerry J.; Zhang, Jin; Lambert, Paul F.; Yang, Peixin; Davis, John S.; Wang, Cheng

doi:10.15252/emmm.201404976

Cited by 225 publications

(218 citation statements)

References 74 publications

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“…3B). Given that YAP expression is increased in high-grade precancerous lesions and cervical squamous cell carcinoma (25) and that E6 was reported to upregulate YAP in cervical cancer cells (26), these results imply that E6 increases TEAD1/4 levels through upregulation of YAP.…”

Section: Figmentioning

confidence: 73%

See 1 more Smart Citation

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.

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Section: Figmentioning

confidence: 73%

“…Although the mechanism is unclear, antiapoptotic and proliferative effects mediated by E6 through p53 inactivation may eventually result in YAP stabilization (26). In contrast, p53 knockdown alone was not sufficient to upregulate TEAD4 and A3B (Fig.…”

Section: Figmentioning

confidence: 98%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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“…Recently, He at al. reported that YAP induces the expression of epidermal growth factor (EGF) receptors including EGFR and ERBB3 in ovarian cell lines [21,22]. …”

Section: Introductionmentioning

confidence: 99%

YAP promotes erlotinib resistance in human non-small cell lung cancer cells

et al. 2016

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Yes-associated protein (YAP) is a main mediator of the Hippo pathway, which promotes cancer development. Here we show that YAP promotes resistance to erlotinib in human non-small cell lung cancer (NSCLC) cells. We found that forced YAP overexpression through YAP plasmid transfection promotes erlotinib resistance in HCC827 (exon 19 deletion) cells. In YAP plasmid-transfected HCC827 cells, GTIIC reporter activity and Hippo downstream gene expression of AREG and CTGF increased significantly (P<0.05), as did ERBB3 mRNA expression (P<0.05). GTIIC reporter activity, ERBB3 protein and mRNA expression all increased in HCC827 erlotinib-resistance (ER) cells compared to parental HCC827 cells. Inhibition of YAP by small interfering RNA (siRNA) increased the cytotoxicity of erlotinib to H1975 (L858R+T790M) cells. In YAP siRNA-transfected H1975 cells, GTIIC reporter activity and downstream gene expression of AREG and CTGF decreased significantly (P<0.05). Verteporfin, YAP inhibitor had an effect similar to that of YAP siRNA; it increased sensitivity of H1975 cells to erlotinib and in combination with erlotinib, synergistically reduced migration, invasion and tumor sphere formation abilities in H1975 cells. Our results indicate that YAP promotes erlotinib resistance in the erlotinib-sensitive NSCLC cell line HCC827. Inhibition of YAP by siRNA increases sensitivity of erlotinib-resistant NSCLC cell line H1975 to erlotinib.

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“…In a cell, phosphorylation of the transcriptional coactivators, Yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ) is controlled by LATS 1/2 which then, regulate cell proliferation, differentiation, and malignant transformation [7]. Hippo pathway has been deregulated in many types of cancer such as breast, lung, liver, colon, cervix, ovary and esophagus [8][9][10][11][12][13]. Regulation of gene expression take place in nucleus by transducing signal from cytoplasm to nucleus.…”

Section: Introductionmentioning

confidence: 99%