Journal Article

The Hippo pathway transcription factors YAP and TAZ play HPV-type dependent roles in cervical cancer

Scarth, James A., Morgan, Ethan L., Theobald, Daisy A., Wang, Miao, Cassidy, Rosa, Macdonald, Andrew, Whitehouse, Adrian, Cogan, Joseph A., Patterson, Molly R., Anene, Chinedu A.

2024

Overview

Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers. The Hippo pathway transcription factors YAP and TAZ are often thought to play redundant roles in cancer progression. Here, Patterson et al demonstrate that TAZ is specifically required in HPV18+ cervical cancer, a subtype associated with worse prognosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/109 / 13/95 / 38 / 38/15 / 38/77 / 38/91 / 631/326/596/2560 / 631/67/395 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Anogenital / Biopsy / Cancer / Carcinogenesis / Carcinogenesis - genetics / Carcinogens / Cell Line, Tumor / Cell migration / Cell Movement / Cell Proliferation / Cervical cancer / Cervical carcinoma / Female / Gene expression / Gene Expression Regulation, Neoplastic / Gene sequencing / Hippo Signaling Pathway / Human papillomavirus / Human papillomavirus 16 - genetics / Human papillomavirus 16 - metabolism / Human papillomavirus 18 - genetics / Human papillomavirus 18 - metabolism / Humanities and Social Sciences / Humans / Malignancy / multidisciplinary / Oral carcinoma / Papillomavirus Infections - genetics / Papillomavirus Infections - metabolism / Papillomavirus Infections - pathology / Papillomavirus Infections - virology / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Coactivator with PDZ-Binding Motif Proteins - metabolism / Tumor cell lines / Uterine Cervical Neoplasms - genetics / Uterine Cervical Neoplasms - metabolism / Uterine Cervical Neoplasms - pathology / Uterine Cervical Neoplasms - virology / YAP-Signaling Proteins - metabolism / Yes-associated protein