Theranostics 2019; 9(3):676-690. doi:10.7150/thno.30224 This issue Cite

Research Paper

TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer

Min Chen1*, Xiu-Jie Sheng3*, Yuan-Yi Qin1*, Song Zhu1, Qing-Xia Wu1,3, Liqing Jia1, Nan Meng1, Yu-Tian He1, Guang-Rong Yan1,2✉

1. Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
2. Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, 511436, China
3. Department of Obstetrics and Gynecology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
*Equal contribution

Citation:
Chen M, Sheng XJ, Qin YY, Zhu S, Wu QX, Jia L, Meng N, He YT, Yan GR. TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer. Theranostics 2019; 9(3):676-690. doi:10.7150/thno.30224. https://www.thno.org/v09p0676.htm
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Abstract

Graphic abstract

Cancer cells undergo metabolic reprogramming to support their energy demand and biomass synthesis. However, the mechanisms driving cancer metabolism reprogramming are not well understood.

Methods: The differential proteins and interacted proteins were identified by proteomics. Western blot, qRT-PCR and IHC staining were used to analyze TBC1D8 levels. In vivo tumorigenesis and metastasis were performed by xenograft tumor model. Cross-Linking assays were designed to analyze PKM2 polymerization. Lactate production, glucose uptake and PK activity were determined.

Results: We established two aggressive ovarian cancer (OVCA) cell models with increased aerobic glycolysis. TBC1D8, a member of the TBC domain protein family, was significantly up-regulated in the more aggressive OVCA cells. TBC1D8 is amplified and up-regulated in OVCA tissues. OVCA patients with high TBC1D8 levels have poorer prognoses. TBC1D8 promotes OVCA tumorigenesis and aerobic glycolysis in a GAP activity-independent manner in vitro and in vivo. TBC1D8 bound to PKM2, not PKM1, via its Rab-GAP TBC domain. Mechanistically, TBC1D8 binds to PKM2 and hinders PKM2 tetramerization to decreases pyruvate kinase activity and promote aerobic glycolysis, and to promote the nuclear translocation of PKM2, which induces the expression of genes which are involved in glucose metabolism and cell cycle.

Conclusions: TBC1D8 drives OVCA tumorigenesis and metabolic reprogramming, and TBC1D8 serves as an independent prognosis factor for OVCA patients.

Keywords: TBC1D, PKM2, aerobic glycolysis, ovarian cancer


Citation styles

APA
Chen, M., Sheng, X.J., Qin, Y.Y., Zhu, S., Wu, Q.X., Jia, L., Meng, N., He, Y.T., Yan, G.R. (2019). TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer. Theranostics, 9(3), 676-690. https://doi.org/10.7150/thno.30224.

ACS
Chen, M.; Sheng, X.J.; Qin, Y.Y.; Zhu, S.; Wu, Q.X.; Jia, L.; Meng, N.; He, Y.T.; Yan, G.R. TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer. Theranostics 2019, 9 (3), 676-690. DOI: 10.7150/thno.30224.

NLM
Chen M, Sheng XJ, Qin YY, Zhu S, Wu QX, Jia L, Meng N, He YT, Yan GR. TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer. Theranostics 2019; 9(3):676-690. doi:10.7150/thno.30224. https://www.thno.org/v09p0676.htm

CSE
Chen M, Sheng XJ, Qin YY, Zhu S, Wu QX, Jia L, Meng N, He YT, Yan GR. 2019. TBC1D8 Amplification Drives Tumorigenesis through Metabolism Reprogramming in Ovarian Cancer. Theranostics. 9(3):676-690.

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