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ZnT7 RNAi favors RafGOFscrib−/−-induced tumor growth and invasion in Drosophila through JNK signaling pathway

Oncogene volume 40, pages 2217–2229 (2021)Cite this article

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Abstract

The disruption of zinc homeostasis has been identified in patients suffering from various cancers, but a causative relationship has not yet been established. Drosophila melanogaster has become a powerful model to study cancer biology. Here using a Drosophila model of malignant tumor RafGOFscrib−/−, we observed that the tumor growth, invasion and migration were enhanced by silencing dZnT7, a zinc transporter localized on the Golgi apparatus. Further study indicated that the zinc deficiency in Golgi of dZnT7 RNAi resulted in ER stress which could activate the c-Jun-N-terminal Kinase (JNK) signaling and this process is mediated by Atg9. Lastly, we demonstrated that the exacerbation of dZnT7 RNAi on tumor was promoted by JNK signaling-dependent cell autonomous and non-autonomous autophagy. These findings suggest that zinc homeostasis in secretory compartments may provide a new therapeutic target for tumor treatment.

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Fig. 1: Zinc transporter ZnT7 controls tumor growth.
Fig. 2: dZnT7 RNAi promotes tumor growth and invasion.
Fig. 3: Zinc dyshomeostasis in Golgi apparatus activates JNK signaling.
Fig. 4: dZnT7 knockdown enhanced tumor growth and invasion depends on JNK signaling.
Fig. 5: The activation of JNK pathway in dZnT7 RNAi induces autophagy which promotes tumor growth, invasion and migration.
Fig. 6: Atg9 could regulate JNK-dependent autophagy activation in dZnT7 RNAi flies.
Fig. 7: A model to explain the effects of zinc transporter ZnT7 on tumor growth and invasion.

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Acknowledgements

This project was funded by the National Natural Science Foundation of China (31671284), the Fundamental Research Funds for the Central Universities (JZ2020HGPA0115), Youth Science and Technology Talents Support Program (2020) by Anhui Association for Science and Technology (RCTJ202001), and the National Postdoctoral Program for Innovative Talents (BX201600045). The authors appreciate the gifts of fly stocks from Dr. Bing Zhou and Dr. Jose C. PASTOR-PAREJA. The authors are also grateful to the Bloomington Drosophila Stock Center, the Vienna Drosophila RNAi Center and Tsinghua Fly Center for fly stocks.

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  1. School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, 230009, China

    Tian Wei, Xiaowen Ji, Yan Gao & Guiran Xiao

  2. School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, China

    Xiaomei Zhu

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Wei, T., Ji, X., Gao, Y. et al. ZnT7 RNAi favors RafGOFscrib−/−-induced tumor growth and invasion in Drosophila through JNK signaling pathway. Oncogene 40, 2217–2229 (2021). https://doi.org/10.1038/s41388-021-01703-x

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