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Nup54-induced CARM1 nuclear importation promotes gastric cancer cell proliferation and tumorigenesis through transcriptional activation and methylation of Notch2

Oncogene volume 41, pages 246–259 (2022)Cite this article

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Abstract

Gastric cancer (GC) has the fifth highest incidence globally, but its molecular mechanisms are not well understood. Here, we report that coactivator-associated arginine methyltransferase 1 (CARM1) is specifically highly expressed in gastric cancer and that its overexpression correlates with poor prognosis in patients with gastric cancer. Nucleoporin 54 (Nup54) was identified as a CARM1-interacting protein that promoted CARM1 nuclear importation. In the nucleus, CARM1 cooperates with transcriptional factor EB (TFEB) to activate Notch2 transcription by inducing H3R17me2 of the Notch2 promoter but not H3R26me2. Additionally, the Notch2 intracellular domain (N2ICD) was identified as a CARM1 substrate. Methylation of N2ICD at R1786, R1838, and R2047 by CARM1 enhanced the binding between N2ICD and mastermind-like protein 1 (MAML1) and increased gastric cancer cell proliferation in vitro and tumor formation in vivo. Our findings reveal a molecular mechanism linking CARM1-mediated transcriptional activation of the Notch2 signaling pathway to Notch2 methylation in gastric cancer progression.

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Fig. 1: CARM1 is highly expressed in gastric cancer.
Fig. 2: CARM1 is required for gastric cancer cell proliferation and tumorigenesis.
Fig. 3: Nup54 interacts with CARM1 and induces its nuclear transport.
Fig. 4: CARM1 activates the Notch2 signaling pathway by inducing H3R17me2 of the Notch2 promoter.
Fig. 5: CARM1 is essential for TFEB transcriptional activation of Notch2.
Fig. 6: Identification of Notch2 as a CARM1 substrate.
Fig. 7: Methylation of N2ICD by CARM1 promotes its binding with MAML1.
Fig. 8: N2ICD methylation promotes cell proliferation and tumorigenesis in gastric cancer.
Fig. 9: Schematic diagram of CARM1 promotes gastric cancer cell proliferation and tumorigenesis.

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Acknowledgements

This study was supported by the fellowship of China Postdoctoral Science Foundation (2021M692679), the special support from Chongqing Postdoctoral Research Institute (7820100607), the National Key Research, and Development Program of China (No.2016YFC1302204 and 2017YFC308600). We thank GEPIA 2 database (http://gepia2.cancer-pku.cn/#survival), TIMER 2.0 database (http://timer.cistrome.org/), Oncomine database (https://www.oncomine.org/resource/login.html) for initial data analysis. We are grateful to PMeS (http://bioinfo.ncu.edu.cn/inquiries_PMeS.aspx) for the prediction of protein methylation sites. Technical support of confocal microscopy from Lei Zhang is greatly appreciated.

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Authors and Affiliations

  1. State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Beibei, Chongqing, 400716, China

    Feng Wang, Jiayi Zhang, Houyi Tang, Xiaoxue Ke, Wen Peng, Shitong Chen, Muhammad nadeem Abbas, Zhen Dong & Hongjuan Cui

  2. Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China

    Feng Wang, Jiayi Zhang, Houyi Tang, Xiaoxue Ke, Wen Peng, Shitong Chen, Muhammad nadeem Abbas, Zhen Dong & Hongjuan Cui

  3. Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing, 404120, China

    Yi Pang

  4. Department of Intensive Care Unit, Harrison International Peace Hospital, Hengshui, 053000, Hebei, China

    Zhaobo Cui

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Contributions

Feng Wang conceived the study, designed and performed the experiments, analyzed the data, and wrote the paper. HC provided suggestions for experiments, reviewed and edited the manuscript. ZC provided suggestions for experiments and assisted with vector construction. MNA and HT assisted with the western blot and ChIP experiments. ZD and SC performed the MS experiment and analyzed the results. JZ and YP performed mice injections. XK and WP performed cell culture, transfection, and infection.

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Correspondence to Zhaobo Cui or Hongjuan Cui.

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Wang, F., Zhang, J., Tang, H. et al. Nup54-induced CARM1 nuclear importation promotes gastric cancer cell proliferation and tumorigenesis through transcriptional activation and methylation of Notch2. Oncogene 41, 246–259 (2022). https://doi.org/10.1038/s41388-021-02078-9

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