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

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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Acknowledgements

We thank Dr. Shimin Zhao from Fudan University for providing expression plasmids for UBR5C, Dr. Tianbang Kang from SUN YAT-SEN University (Guangzhou, China) for providing K30, K140, K410 and K520 cells and Dr. Zhihua Liu at Cancer Hospital Chinese Academy of Medical Sciences (Beijing, China) for providing K70, K150, K450 and K510 cells. We also thank members of Wong’s lab for valuable discussion. This study is supported by grants from the National Natural Science Foundation of China (81530078), the Ministry of Science and Technology of China (2017YFA0504201 and 2015CB910402 to J.W.) and the Grants from the State Key Laboratory of Oncogenes and Related Genes (No. 90-17-05).

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Correspondence to Jiwen Li or Jiemin Wong.

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