Gli1 interacts with YAP1 to promote tumorigenesis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the predominant esophageal cancer type in China. The aberrant activation of glioma-associated oncogene homolog1 (Gli1), a key factor in Hedgehog (Hh) signaling pathway, has been found in esophageal carcinoma. Moreover, Yes-associated protein 1 (YAP1), the major mediator of Hippo signaling pathway, has been linked to esophageal carcinoma progression. However, the precise roles and the underlying mechanism of both Gli1 and YAP1 in ESCC are unclear. Here, we found that Gli1 and YAP1 are overexpressed in ESCC and are associated with poor prognosis. In addition, we confirmed that knockdown of Gli1 or YAP1 suppresses ESCC cell growth, migration, and invasion in ESCC TE1 and EC109 cells. Significantly, Gli1 interacts with YAP1 in ESCC cells. Both Gli1 and YAP1 proteins are closely correlated with each other in human ESCC samples. Mechanistically, Gli1 upregulates YAP1 in a LATS1-independent manner. Conversely, YAP1 induces Gli1 by regulating phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Most importantly, we demonstrated that the interaction between Gli1 and YAP1 promotes ESCC tumor growth in vitro and in vivo. Our findings established a novel signaling mechanism by which the interaction between Gli1 and YAP1 promotes ESCC cell growth. This signaling regulation of the tumorigenesis provides a new therapeutic strategy for highly lethal ESCC.

Wang C ，Cheng L ，Song S ，Wu S ，Sun G ... -  《-》

SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma.

Whether SOX2 and ACTL6A/TP63 interact with the Hippo-YAP1 pathway in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples. Multiple SOX2 binding peaks in the locus of WWC1, a Hippo-YAP1 regulator, and an inverse correlation between the expression of SOX2 and WWC1 are identified, suggesting direct repression of WWC1 by SOX2. Expression scores of SOX2 are higher in tumors than normal tissues and positively correlated with nuclear YAP1 staining in primary ESCC. Moreover, SOX2 gain-of-function significantly promotes nuclear YAP1 expression in ESCC cells while silencing of SOX2 expression inhibits YAP1 activation. SOX2 overexpression leads to a significant enhancement of cell migration and invasion as well as chemoresistance to cisplatin, whereas knockdown of SOX2 or ectopic expression of WWC1 suppresses the SOX2-induced migration ability and invasive potential. Disruption of this SOX2-WWC1-YAP1 axis could be a therapeutic strategy for SOX2-dependent tumors.

Chai Y ，Li Q ，Zhao H ，Zhang Z ，Yu X ，Pang L ，Liu Z ，Zhao J ，Wang L ，Li F ... -  《Cancer Medicine》

[En1 promotes cell proliferation and migration via Hedgehog signaling pathway in esophageal squamous cell carcinoma].

Zhao N ，Gong TY ，Wei ZC ，Cong J ，Liu ZH ，Chen HY ... -  《-》

The interaction of TEA domain transcription factor 4 (TEAD4) and Yes-associated protein 1 (YAP1) promoted the malignant process mediated by serum/glucocorticoid regulated kinase 1 (SGK1).

He S ，Zhang H ，Xiao Z ，Bhushan S ，Gao K ，Wang W ... -  《-》

Gli1, a potential regulator of esophageal cancer stem cell, is identified as an independent adverse prognostic factor in esophageal squamous cell carcinoma.

Yang Z ，Cui Y ，Ni W ，Kim S ，Xuan Y ... -  《-》