2. Academic Validation
  3. AKT drives SOX2 overexpression and cancer cell stemness in esophageal cancer by protecting SOX2 from UBR5-mediated degradation

AKT drives SOX2 overexpression and cancer cell stemness in esophageal cancer by protecting SOX2 from UBR5-mediated degradation

  • Oncogene. 2019 Jun;38(26):5250-5264. doi: 10.1038/s41388-019-0790-x.
Zhen Wang 1,  Li Kang 1,  Huifang Zhang 1,  Yuanyong Huang 1,  Lan Fang 1 2,  Menghan Li 1,  Peter J Brown 3,  Cheryl H Arrowsmith 3,  Jiwen Li 4,  Jiemin Wong 5 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2 Shanghai Tenth People's Hospital of Tongji University, School of Medicine and School of Life Science and Technology, Tongji University, Shanghai, 200072, China.
  • 3 Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. jwli@bio.ecnu.edu.cn.
  • 5 Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. jmweng@bio.ecnu.edu.cn.
  • 6 State Key Laboratory of Oncogene and Related Genes, Shanghai, China. jmweng@bio.ecnu.edu.cn.
PMID: 30894683 DOI: 10.1038/s41388-019-0790-x
Abstract

As a transcription factor critical for embryonic and adult stem cell self-renewal and function, SOX2 gene amplification has been recognized as a driving factor for various cancers including esophageal Cancer. SOX2 overexpression occurs more broadly in Cancer than gene amplification, but the mechanism is poorly understood. Here we showed that in esophageal Cancer cell lines the levels of SOX2 proteins are not directly correlated to the copy numbers of SOX2 genes and are strongly influenced by proteostasis. We showed that Akt is a major determinant for SOX2 overexpression and does so by protecting SOX2 from ubiquitin-dependent protein degradation. We identified UBR5 as a major ubiquitin E3 Ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115. Phosphorylation of SOX2 at threonine 116 by Akt inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2. We provided evidence that Akt Inhibitor can effectively downregulate SOX2 and suppress esopheageal Cancer cell proliferation and stemness. Taken together, our study provides new insight into the mechanism of SOX2 overexpression in Cancer and evidence for targeting Akt as a potential therapeutic strategy for SOX2-positive cancers.

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