2. Academic Validation
  3. GSK3β-driven SOX2 overexpression is a targetable vulnerability in esophageal squamous cell carcinoma

GSK3β-driven SOX2 overexpression is a targetable vulnerability in esophageal squamous cell carcinoma

  • Oncogene. 2023 Jun 22. doi: 10.1038/s41388-023-02748-w.
Li Kang # 1 2,  Yujie Liu # 3,  Jianzhong He # 4,  Yaling Wang 1,  Mengyang Xue 5 6,  Xin Wu 1,  Zhen Wang 7,  Yunpeng Zhang 1,  Manyu Chu 4,  Jialun Li 1,  Wei Wei 1,  Jiwen Li 1,  Enmin Li 8,  Lujian Liao 1,  Jianru Xiao 3,  Rong Zhang 6,  Liyan Xu 9,  Jiemin Wong 10 11
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 2 Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai, China.
  • 3 Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 4 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China.
  • 5 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 6 Department of Obstetrics and Gynecology, Fengxian Central Hospital affiliated to the Southern Medical University, Shanghai, China.
  • 7 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 8 Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, China.
  • 9 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China. lyxu@stu.edu.cn.
  • 10 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. jmweng@bio.ecnu.edu.cn.
  • 11 Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai, China. jmweng@bio.ecnu.edu.cn.
  • # Contributed equally.
PMID: 37349645 DOI: 10.1038/s41388-023-02748-w
Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest forms of human malignancy that currently lacks approved targeted therapeutics. Accumulating evidence suggests that SOX2 overexpression is a key driving factor for ESCC and various squamous cell carcinoma. Here, through screening a small-molecule kinase inhibitor library, we identified GSK3β as a kinase that is critically required for robust SOX2 expression in ESCC cells. GSK3β did not promote SOX2 transcriptionally but was required for SOX2 protein stability. We demonstrated that GSK3β interacts with and phosphorylates SOX2 at residue S251, which blocks SOX2 from ubiquitination and proteasome-dependent degradation instigated by ubiquitin E3 Ligase CUL4ADET1-COP1. Pharmacological inhibition or knockdown of GSK3β by RNA interference selectively impaired SOX2-positive ESCC cell proliferation, Cancer stemness, and tumor growth in mouse xenograft model, suggesting that GSK3β promotes ESCC tumorigenesis primarily by driving SOX2 overexpression. GSK3β was found to be frequently overexpressed in clinical esophageal tumors, and there was a positive correlation between GSK3β and SOX2 protein levels. Notably, we found that SOX2 enhanced GSK3β expression transcriptionally, suggesting the existence of a vicious cycle that drives a coordinated GSK3β and SOX2 overexpression in ESCC cells. Finally, we demonstrated in tumor xenograft model that GSK3β inhibitor AR-A014418 was effective in suppressing SOX2-positive ESCC tumor progression and inhibited tumor progression cooperatively with chemotherapeutic agent carboplatin. In conclusion, we uncovered a novel role for GSK3β in driving SOX2 overexpression and tumorigenesis and provided evidence that targeting GSK3β may hold promise for the treatment of recalcitrant ESCCs.

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