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Gamma-glutamyltransferase 7 suppresses gastric cancer by cooperating with RAB7 to induce mitophagy

Oncogene volume 41, pages 3485–3497 (2022)Cite this article

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Abstract

We identified gamma-glutamyltransferase 7 (GGT7) to be frequently downregulated in gastric cancer, but its role remains unknown. Here we elucidated the clinical significance, functional roles, and molecular mechanism of GGT7 in gastric cancer. GGT7 was downregulated by promoter methylation and restored by demethylation treatment in gastric cancer cells. GGT7 methylation inversely correlated with mRNA expression in gastric tumors (n = 221; r = −0.686, P < 0.0001). High-expression of GGT7 in adjacent non-tumor tissues was significantly associated with favorable survival in gastric cancer patients (n = 138; P = 0.009), and was an independent prognostic factor by multivariate Cox regression (HR = 0.381, P < 0.05). GGT7 significantly inhibited gastric cancer cell growth, G1-S transition, and migration and invasion abilities. GGT7 also significantly attenuated the growth of subcutaneous xenograft tumors and reduced metastasis to the lung in nude mice. The mitophagy regulator RAB7 was identified as a direct downstream co-player of GGT7 by co-immunoprecipitation followed by mass spectrometry. Growth suppression effect of GGT7 was at least partly dependent on RAB7 by rescue experiments. GGT7 induced autophagy as shown by electron microscopy and confirmed by the increased LC3B and decreased p62. GGT7 recruited RAB7 by direct binding and drove RAB7 to translocate from nucleus to cytoplasm, subsequently mediating mitophagy by increasing mitophagy mediators/inducers. GGT7 inhibited intracellular ROS, which was associated with increased mitophagy, and subsequently suppressed MAPK signaling. Collectively, GGT7 plays a pivotal tumor-suppressing role in gastric cancer by directly binding with RAB7 to induce mitophagy and inhibit ROS and MAPK cascades. GGT7 is an independent prognostic factor for gastric cancer patients.

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Fig. 1: GGT7 is downregulated by promoter methylation in gastric cancer.
Fig. 2: GGT7 exerts tumor-suppressive function in gastric cancer cells.
Fig. 3: GGT7 overexpression inhibited subcutaneous tumorigenicity and metastasis in vivo.
Fig. 4: GGT7 dysregulated MAPK signaling.
Fig. 5: GGT7 interacts with RAB7 to exert tumor-suppressive function.
Fig. 6: GGT7 promoted mitophagy but not cell apoptosis and dysregulated ROS process.
Fig. 7: GGT7 mediated mitophagy to exert its tumor-suppressive role.

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Acknowledgements

The project was supported by the RGC-GRF Hong Kong (14116418), National Nature and Science Foundation of China (81773000), RGC-GRF Hong Kong (C7065-18GF), and Vice-Chancellor’s Discretionary Fund CUHK.

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Authors and Affiliations

  1. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China

    Xiaohong Wang, Francis K. L. Chan, Jun Yu & Jessie Qiaoyi Liang

  2. Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China

    Xiaohong Wang, Lianhai Zhang & Jiafu Ji

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  1. Xiaohong Wang
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Contributions

JQL and JY conceived and designed the study. XW, JQL, and LZ contributed to the carrying out of the experiments. XW, JQL, FKLC, and JJ contributed to the data analysis. XW and JQL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jiafu Ji, Jun Yu or Jessie Qiaoyi Liang.

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Wang, X., Zhang, L., Chan, F.K.L. et al. Gamma-glutamyltransferase 7 suppresses gastric cancer by cooperating with RAB7 to induce mitophagy. Oncogene 41, 3485–3497 (2022). https://doi.org/10.1038/s41388-022-02339-1

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