New insights in Hippo signalling alteration in human papillomavirus-related cancers

Olmedo-Nieva, Leslie; Muñoz-Bello, J. Omar; Manzo-Merino, Joaquín; Lizano, Marcela

doi:10.1016/j.cellsig.2020.109815

“…Genotype-specific differences could also explain the stronger effect of TEADi on HPV18 E7 in lifespan extension assays ( Figure 6 ). Although other reports have suggested that HPV might activate YAP1 ( He et al, 2015 ; Morgan et al, 2020 ; Olmedo-Nieva et al, 2020 ; Webb Strickland et al, 2018 ), no specific activity of an HPV protein has previously been shown to enable YAP1 activation. Other groups have proposed that HPV E6 activates YAP1 ( He et al, 2015 ; Webb Strickland et al, 2018 ), and we observed modest YAP1 activation by HPV E6 compared to E7.…”

Section: Discussionmentioning

confidence: 90%

YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia

Hatterschide

¹

,

Castagnino

²

,

Kim

³

et al. 2022

eLife

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Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly five percent of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector YAP1. The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 bind and degrade the tumor suppressor PTPN14. E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.

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“…Genotype-specific differences could also explain the stronger effect of TEADi on HPV18 E7 in lifespan extension assays (Figure 6). Although other reports have suggested that HPV might activate YAP1 (He et al, 2015;Morgan et al, 2020;Olmedo-Nieva et al, 2020;Webb Strickland et al, 2018), no specific activity of an HPV protein has previously been shown to enable YAP1 activation. Other groups have proposed that HPV E6 activates YAP1 (He et al, 2015;Webb Strickland et al, 2018), but we did not observe YAP1 activation by HPV E6.…”

Section: Discussionmentioning

confidence: 90%

YAP1 Activation by Human Papillomavirus E7 Promotes Basal Cell Identity in Squamous Epithelia

Hatterschide

¹

,

Castagnino

²

,

Kim

³

et al. 2021

Preprint

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Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly five percent of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector YAP1. The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 bind and degrade the tumor suppressor PTPN14. E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.

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“…Currently, Hippo signalling has emerged as one of the key pathways being altered frequently in HPV-related cancers (Olmedo-Nieva et al, 2020). It has been suggested that high-risk E6 requires the PDZ motif to promote YAP nuclear localisation in serum-starved keratinocytes (Webb Strickland et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Previous literature has indicated that E6 protein as a homeostasis regulator during productive infection, and in both the high and low-risk Alpha types, can regulate p53 and thus indirectly Notch-mediated epithelial differentiation (Khelil et al, 2021; Kranjec et al, 2017; Murakami et al, 2019; Yugawa et al, 2007). Moreover, accumulating evidence suggests that E6 modulates epithelial homeostasis through interacting with key molecules involved in WNT, NOTCH and HIPPO signalling (Gupta et al, 2018; Lichtig et al, 2010; Olmedo-Nieva et al, 2020; Sominsky et al, 2014). There is increasing evidence that the HIPPO pathway effector yes-associated protein (YAP) plays pivotal role in controlling epidermal homeostasis and high-risk E6 has been shown to control YAP nucleus-cytoplasm shift to activate YAP transcriptional activity (He et al, 2015; Webb Strickland et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

E6AP is important for HPV E6’s role in regulating epithelial homeostasis and its loss impairs keratinocyte commitment to differentiation

Yin

¹

,

Egawa

²

,

Zheng

³

et al. 2022

Preprint

0

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Human papillomaviruses (HPV) typically cause chronic infections by modulating homeostasis of infected basal cell to ensure persistence. Using FUCCI and cell-cell competition assays, we established the role of two common viral targets of low-risk and high-risk E6 proteins, E6AP and NHERF1, on four key components of epithelial homeostasis. These includes cell density, proliferation, commitment to differentiation and basal layer delamination. Our RNA sequencing results validated E6 effects on homeostasis and revealed similar transcriptional gene regulation of E6-expressing cells and E6AP-/- cells. For example, yes-associated protein (YAP) target genes were up-regulated by either E6 expression or E6AP depletion. This is also supported by YAP expression pattern in both monolayer cell culture and HPV-infected clinical tissues. As the conserved binding partner of Alpha group HPV E6 proteins, the precise role of E6AP in modulating keratinocyte phenotype and associated signalling pathways have not been defined. We demonstrate that deletion of E6AP in keratinocytes delayed the onset of differentiation and the abundance of E6AP is reduced in HPV-infected tissue. This suggests that Alpha E6 regulates epithelium homeostasis by inhibiting E6AP activity, leading to alteration of multiple downstream pathways including YAP activation. Potential treatments can thus be developed to resolve the reservoir of HPV infection.

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New insights in Hippo signalling alteration in human papillomavirus-related cancers

Cited by 9 publications

References 187 publications

YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia

YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia

YAP1 Activation by Human Papillomavirus E7 Promotes Basal Cell Identity in Squamous Epithelia

E6AP is important for HPV E6’s role in regulating epithelial homeostasis and its loss impairs keratinocyte commitment to differentiation

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