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

Abstract

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.

The role of Hippo‐YAP signaling in squamous cell carcinomas

“…Each of these factors has been shown to activate YAP1 directly in 1 or more SSE cell types 62‐64 . In addition, as detailed above, loss‐of‐function or gain‐of‐function mutations of genes that result in YAP activation are linked to SCCs 62,65‐67 . When these gene mutations combine with carcinogens, YAP1 activity rises even higher 33,42 .…”

“…[62][63][64] In addition, as detailed above, loss-of-function or gain-of-function mutations of genes that result in YAP activation are linked to SCCs. 62,[65][66][67] When these gene mutations combine with carcinogens, YAP1 activity rises even higher. 33,42 In short, there is substantial evidence supporting our hypothesis that, for many SCCs, the original CIS Conversely, all EGF-like ligands can apparently activate YAP1, 62 so that an autocrine loop related to YAP1-EGF/EGFR signaling may stimulate SCC genesis and progression.…”

Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

“…Other read-outs for cancer stemness associated genes such as BMI-1 [ 61 ], Nanog [ 58 , 59 , 60 ], Sox2 [ 53 , 54 , 55 , 56 , 57 ], Oct-4 [ 54 , 62 , 65 , 66 ], SALL4 [ 55 , 73 ], GLI-1 [ 70 , 71 , 72 ], Ep-CAM [ 67 , 68 , 69 ], and Podoplanin (PDPN) [ 74 , 75 , 76 , 77 ] are involved in regulating CSC populations, leading to enhanced proliferation, invasiveness, therapy resistance, and metastatic capacity. They could potentially act as prognostic CSC markers in esophageal cancer.…”

FAT1 and PTPN14 Regulate the Malignant Progression and Chemotherapy Resistance of Esophageal Cancer through the Hippo Signaling Pathway

“…Yes-associated protein (Yap) is an important target of the Hippo signaling pathway. Under normal circumstances, the activity of the Hippo-Yap signaling pathway is strictly regulated, and once the pathway is out of balance, it will lead to the occurrence and development of a variety of diseases and even malignant tumors [ 8 – 10 ]. Yap1, a major effector and regulatory protein in the classical Hippo-YAP signaling pathway, regulates the expression of several target genes by entering into the nucleus as a transcriptional coactivated form.…”