YAP1 is a potent driver of the onset and progression of oral squamous cell carcinoma

Abstract

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of Mob1a/b and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive SCC within 4 weeks. In humans, precancerous tongue dysplasia displays YAP1 activation correlating with reduced patient survival. Combinations of molecules mutated in OSCC may increase and sustain YAP1 activation to the point of oncogenicity. Strikingly, siRNA or pharmacological inhibition of YAP1 blocks murine OSCC onset in vitro and in vivo. Our work justifies targeting YAP1 as therapy for OSCC and perhaps HNSCC, and our mouse model represents a powerful tool for evaluating these agents.

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

“…However, this was not seen in HNSCC tumor samples and cell lines ( Ge et al, 2011 ), suggesting a cancer/context-specific regulatory mechanism might be in place. Consistent with the oncogenic roles of YAP1 reported in OSCC ( Hiemer et al, 2015 ; Omori et al, 2020 ), another study showed that p63, together with the co-expressing chromotin remodeling factor, ACTL6A, can drive YAP1 activation, suppressing differentiation and promoting cell proliferation in HNSCC ( Saladi et al, 2017 ). Similar observations between WWTR1 and TP63 have not been reported thus far.…”

“…Analysis of genome-wide transcriptional changes upon knockdown of YAP1 or WWTR1 in OSCC showed that YAP1 had a more prominent role in transcriptional regulation ( Hiemer et al, 2015 ). Using a tongue orthotopic mouse model with the deletion of MOB1A/B, Omori et al, 2020 provided strong evidence that YAP1 acted as a strong driver in OSCC tumor initiation and progression, whereby WWTR1 did not seems to play an equivalent role ( Omori et al, 2020 ). The differences between YAP1 and WWTR1 can also be further exemplified in terms of their interaction with upstream/downstream pathways, that would involve other frequently co-amplified genes such as PIK3CA, TP63 , and SOX2 .…”

YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation

“…Inactivation of the Hippo pathway induces YAP/TAZ nuclear translocation, thereby inducing transcriptional targets and promoting cell proliferation [10][11][12][13][14][15][16][17]. YAP/-TAZ siRNA and treatment with simvastatin, a YAP inhibitor [36,37], reduced not only the mRNA levels of ankyrin repeat domain 1 (ANKRD1) and cellular communication network factor 1 (CCN1; also known as CYR61), which are transcriptional targets of YAP/TAZ, but also 2D proliferation of HSC-4 cells (supplementary material, Figure S1A). These loss-of-function experiments indicated that YAP/TAZ signaling was involved in HSC-4 cell proliferation.…”

The potential role of YAP in head and neck squamous cell carcinoma

“…Tissue-specific knockout of the YAP and TAZ genes from the basal cell layer of the mouse skin suppresses the formation of papilloma and squamous cell carcinoma induced by chemical carcinogens 72 . Remarkably, the activation of YAP in the tongue through inducible deletion of the Mob1a and Mob1b genes causes the development of carcinoma in situ within 2 weeks and invasive squamous cell carcinoma within 4 weeks 67 . Tumorigenesis induced by Mob1a/b deletion is not affected by the loss of the TAZ gene, suggesting that YAP plays a major role in this genetic context.…”