Aberrant Ubiquitin Ligase CHIP Nuclear Export Promotes SOX2 Overexpression In Esophageal Squamous Cell Carcinoma

Esophageal cancer is malignant tumor occurred in the esophageal track.The incidence and mortality of esophageal squamous cell carcinoma have remained high,especially in East Asia and China.To provide more effective therapeutic treatment and strategy for esophageal squamous cell carcinoma,there is a urgent need to clarify the underlying pathogenic mechanism of the disease.A large number of studies have found that the transcription factor SOX2 plays a very important role in the occurrence and development of a variety of cancers.In esophageal squamous cell carcinoma,elevated SOX2 proteins have been shown to promote cell proliferation,invasion,migration and tumor stem cell function.This thesis mainly focused on the regulation of SOX2 protein stability,aiming to inhibit esophageal squamous cell carcinoma by downregulating the SOX2 protein level.Our previous studies have shown that in mouse embryonic stem cells E3 ubiquitin ligase WWP2 can target SOX2 degradation through ubiquitin proteasome pathway and that in esophageal squamous cells E3 ubiquitin ligase UBR5 can also mediate the proteasome degradation of SOX2.To identify additional E3 ligases that also regulate SOX2 protein stability,we screened all E3 ligases that have been shown to interact with SOX2.We found that E3 ubiquitin ligase CHIP ubiquitinates SOX2 and negatively regulates SOX2 protein stability in esophageal squamous cell carcinoma cells in a molecular chaperone HSP70-dependent manner.Immunohistochemical analysis of paired adjacent control tissues and squamous cell carcinomas revealed that CHIP was selectively accumulated in the cytoplasm and essentially devoid in the nucleus in esophageal squamous cell carcinoma in comparison to the adjacent control tissues.We found that CHIP targets SOX2 degradation in the nucleus and the aberrant cytoplasm localization of CHIP promotes SOX2 overexpression and tumorigenesis.Furthermore,we found that CHIP promotes tumor cell proliferation and the formation of tumor stem cells by regulating the protein level of SOX2.Finally,we demonstrated that CHIP overexpression suppressed esophageal squamous cell carcinoma growth and development in mice through a xenograft mouse model.In summary,this study has revealed how E3 ubiquitin ligase CHIP negatively regulates the stability of SOX2 protein and aberrant CHIP cytoplasm localization may enhance SOX2 protein level in esophageal squamous cell carcinoma.Our study also provides a potential new therapeutic target for esophageal squamous cell carcinoma.