Theranostics 2021; 11(16):8112-8128. doi:10.7150/thno.54961

Research Paper

CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer

Tongyuan Deng1, Peng Shen2,3, Aimin Li1, Ziyan Zhang1, Huiling Yang5, Xiaojie Deng1, Xuemei Peng1, Zhe Hu1, Zibo Tang1, Jiahao Liu1, Rentao Hou1, Zhen Liu1,4✉, Weiyi Fang1✉

1. Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315 Guangzhou, China.
2. Cancer Institute, Southern Medical University, 510515 Guangzhou, China.
3. Department of Oncology, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China.
4. Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, 511436 Guangzhou, China.
5. School of Pharmacy, Guangdong Medical University, 523808 Dongguan, China.
These authors contributed equally: Tongyuan Deng, Peng Shen, Aimin Li, Ziyan Zhang.

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Citation:
Deng T, Shen P, Li A, Zhang Z, Yang H, Deng X, Peng X, Hu Z, Tang Z, Liu J, Hou R, Liu Z, Fang W. CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer. Theranostics 2021; 11(16):8112-8128. doi:10.7150/thno.54961. Available from https://www.thno.org/v11p8112.htm

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Abstract

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer.

Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated.

Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells.

Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.

Keywords: Gastric cancer, CCDC65, ENO1, AKT1, Metformin