VGLL4 inhibits YAP1/TEAD signaling to suppress the epidermal squamous cell carcinoma cancer phenotype.
Epidermal squamous cell carcinoma (SCC) develops in response to ultraviolet light exposure and is among the most common cancers. The transglutaminase 2 cancer cell survival protein stimulates the activity of the YAP1/TEAD transcription complex to drive the expression of genes that promote aggressive epidermal SCC cell invasion, migration, and tumor formation. Therefore, we are interested in mechanisms that may inhibit these events. Vestigial-like protein-4 (VGLL4) is a transcription cofactor/tumor suppressor that inhibits several pro-cancer pathways including YAP1 signaling. Our present studies show that VGLL4 inhibits YAP1/TEAD-dependent transcription to reduce the expression of YAP1 target genes (CCND1, CYR61, and CTGF) and pro-cancer collagen genes (COL1A2 and COL3A1). We further show that loss of these YAP1 regulated genes is required for VGLL4 suppression of the cancer cell phenotype, as forced CCND1 or COL1A2 expression partially restores the aggressive cancer phenotype in VGLL4 expressing cells. Consistent with these findings, VGLL4 expression reduces tumor formation, and this is associated with reduced CCND1, CYR61, CTGF, COL1A2, and COL1A3 mRNA and protein levels, and reduced EMT marker expression. These findings indicate that VGLL4 suppresses the malignant epidermal SCC cancer phenotype by inhibiting YAP1/TEAD-dependent pro-cancer signaling.
['Mickle|McKayla|M|', 'Adhikary|Gautam|G|', 'Shrestha|Suruchi|S|', 'Xu|Wen|W|', 'Eckert|Richard L|RL|0000-0002-3770-4779']
D048868:Adaptor Proteins, Signal Transducing D002294:Carcinoma, Squamous Cell D045744:Cell Line, Tumor D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D010641:Phenotype D012878:Skin Neoplasms D014157:Transcription Factors D023041:Xenograft Model Antitumor Assays D000091102:YAP-Signaling Proteins
TEAD epidermal squamous cell carcinoma transglutaminase 2 CCND1 CYR61 COL1A2 COL3A1 CTFG Hippo signaling TAZ YAP cancer stem cell