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

The persistent infection with high-risk human papillomavirus (HPV) is an etiologic factor for the development of different types of cancers, mainly attributed to the continuous expression of E6 and E7 HPV oncoproteins, which regulate several cell signalling pathways including the Hippo pathway. It has been demonstrated that E6 proteins promote the increase of the Hippo elements YAP, TAZ and TEAD, at protein level, as well as their transcriptional targets. Also, E6 and E7 oncoproteins promote nuclear YAP localization and a decrease in YAP negative regulators such as MST1, PTPN14 or SOCS6. Interestingly, Hippo signalling components modulate HPV activity, such as TEAD1 and the transcriptional co-factor VGLL1, induce the activation of HPV early and late promoters, while hyperactivation of YAP in specific cells facilitates virus infection by increasing putative HPV receptors and by evading innate immunity. Additionally, alterations in Hippo signalling elements have been found in HPV-related cancers and particularly, the involvement of HPV oncoproteins on the regulation of some of these Hippo components has been also proposed, although the precise mechanisms remain unclear. The present review addresses the recent findings describing the interplay between HPV and Hippo signalling in HPV-related cancers, a fact that highlights the importance of developing more in-depth studies in this field to establish key therapeutic targets.