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.

中文翻译：

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VGLL4 抑制 YAP1/TEAD 信号传导以抑制表皮鳞状细胞癌的癌症表型

表皮鳞状细胞癌 (SCC) 会随着紫外线照射而发展，是最常见的癌症之一。转谷氨酰胺酶 2 癌细胞存活蛋白刺激 YAP1/TEAD 转录复合物的活性，以驱动促进侵袭性表皮 SCC 细胞侵袭、迁移和肿瘤形成的基因表达。因此，我们对可能抑制这些事件的机制感兴趣。Vestigial-like protein-4 (VGLL4) 是一种转录辅因子/肿瘤抑制因子，可抑制包括 YAP1 信号在内的多种促癌途径。我们目前的研究表明，VGLL4 抑制 YAP1/TEAD 依赖性转录以降低 YAP1 靶基因（CCND1、CYR61 和 CTGF）和促癌胶原基因（COL1A2 和 COL3A1）的表达。我们进一步表明，这些 YAP1 调节基因的缺失是 VGLL4 抑制癌细胞表型所必需的，因为强制 CCND1 或 COL1A2 表达部分恢复了 VGLL4 表达细胞中的侵袭性癌症表型。与这些发现一致，VGLL4 表达减少了肿瘤形成，这与 CCND1、CYR61、CTGF、COL1A2 和 COL1A3 mRNA 和蛋白质水平降低以及 EMT 标志物表达降低有关。这些发现表明，VGLL4 通过抑制 YAP1/TEAD 依赖性促癌信号传导来抑制恶性表皮 SCC 癌表型。这与 CCND1、CYR61、CTGF、COL1A2 和 COL1A3 mRNA 和蛋白质水平降低以及 EMT 标志物表达降低有关。这些发现表明，VGLL4 通过抑制 YAP1/TEAD 依赖性促癌信号传导来抑制恶性表皮 SCC 癌表型。这与 CCND1、CYR61、CTGF、COL1A2 和 COL1A3 mRNA 和蛋白质水平降低以及 EMT 标志物表达降低有关。这些发现表明，VGLL4 通过抑制 YAP1/TEAD 依赖性促癌信号传导来抑制恶性表皮 SCC 癌表型。