Abstract B16: Transcriptional addiction to YAP1—the major driving force of oral cancer carcinogenesis and evolution

Background: In this era of precision medicine, the clinically effective molecular target of HNSCC has not been identified so far. This is mainly because the predominant genetic alterations in HNSCC are loss-of-function (LOF) mutations in tumor suppressor genes (TSGs), which are generally undruggable targets. We hypothesized that certain effector molecules liberated from the TSGs restriction may play an essential role in HNSCC oncogenesis and evolution. In this context, we analyzed the oncogenic function of transcription coactivator YAP1, the essential downstream effector protein of the Hippo pathway. Experiments and Results: We first examined the effect of mouse tongue epithelium specific conditional double knockout (cDOK) of Mob1a/b, the core component of the Hippo pathway that inhibits YAP1, employing CreERT; Mob1aflox/flox; Mob1b−/−mouse. Consequent YAP1 activation (but not TAZ) developed extremely rapid and highly reproducible (100%) tongue tumors: carcinoma in situ (2 weeks) and invasive carcinoma (4 weeks). The tongue epithelium cells isolated from the cDOK mouse demonstrated YAP1-dependent aggressive phenotypes. In human oral HNSCC samples, expanding accumulation of nuclear YAP1 protein was observed from the basal stem/progenitor cells to invasive cancer cells and this spreading overexpression was significantly correlated with poor prognosis of patients. The YAP1 target module expression, established thorough the microarray assays with cDKO mouse cells, also correlated with the unfavorable prognosis of patients in the TCGA data. To elucidate epigenetic mechanism that underlies this extremely rapid carcinogenesis, we then conducted chip-seq for cDKO mouse cells with or without YAP1 activation. Our preliminary data indicated that YAP1-targeted genes predominantly reside in the euchromatin islands and, surprisingly, their enhancers are marked with active H3K27ac, even in the YAP1-off condition, thus ready to respond to YAP1 nuclear translocation and thereby to start transcription, contradicting our expectation that that genome-wide chromatin remodeling must be required in this rapid carcinogenesis model. Given that the presumed physiologic roles of YAP1 are a monitor of microenvironment and an emitter of regenerative cue under emergent cellular stressors (e.g., tissue injury) in the normal stem/progenitor cells, it is plausible that YAP1-target genes are kept in the ready-to-go status and constitutive activation of YAP1 and subsequent expression of targeted genes lead to the rapid carcinogenesis, causing the condition of “wounds that never heal.” Finally, our data and a recent study by Prof. Gutkind’s laboratory indicate that the major LOF of TSGs (e.g., p53 and FAT1) in HNSCC may convergently lead to the liberation of YAP1 activity. Conclusions: Collectively, our data suggest that for both the onset and the evolution, HNSCC might be highly dependent on (i.e., addicted to) the activation of YAP1-induced transcription. Citation Format: Muneyuki Masuda, Hirofumi Omori, Kuniaki Sato, Kenichi Taguchi, Masashige Bando, Satoshi Toh, Katsuhiko Shirahige, Koshi Mimori, Akira Suzuki. Transcriptional addiction to YAP1—the major driving force of oral cancer carcinogenesis and evolution [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B16.