Abstract LB212: The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype

Abstract

Abstract Epidermal squamous cell carcinoma (SCC) is among the most common and aggressive forms of cancer. We previously showed that the pro-cancer transcription factor, YAP1, drives an aggressive SCC cancer phenotype by binding to nuclear TEAD transcription factors to activate pro-cancer gene expression. Vestigial-like protein 4 (VGLL4) is a tumor suppressor that is downregulated in epithelial cancers. It binds to TEAD factors to displace YAP1 binding to reduce YAP1-dependent transcription and target gene expression. The present study shows that VGLL4 overexpression reduces SCC cell TEAD-dependent transcription to reduce expression of mRNA and protein encoding YAP1-target genes (CTGF, CYR61, CCND1), and pro-cancer collagen genes (COL1A2, COL3A1) leading to reduced cell proliferation, spheroid formation, invasion and migration. Identical results were observed in response to transient and stable VGLL4 overexpression. Similarly, VGLL4 expression reduces YAP1 activity in tumors leading to reduced YAP1 target and pro-cancer collagen gene expression and reduced and EMT marker proteins levels which is associated with reduced tumor formation. Loss of YAP1 responsive gene expression appears to be essential for VGLL4 attenuation of the aggressive phenotype, as forced overexpression of CCND1 or COL1A2 antagonizes VGLL4 action. These findings suggest VGLL4 functions as a tumor suppressor in SCC by repressing YAP1/TEAD signaling and consequently attenuating the SCC phenotype. Citation Format: McKayla B. Mickle, Gautam Adhikary, Wen Xu, Suruchi Shrestha, Richard L. Eckert. The VGLL4 tumor suppressor inhibits transglutaminase-2 dependent YAP1-TEAD signaling to attenuate the cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB212.