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The splicing factor SRRM2 modulates two S6K kinases to promote colorectal cancer growth

Oncogene volume 44, pages 1284–1299 (2025)Cite this article

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Abstract

The mechanistic target of rapamycin (mTOR) pathway plays a critical role in cell growth and metabolic homeostasis. The ribosomal protein S6 kinases S6K1 and S6K2 are the major effectors of the mTOR pathway key to translation efficiency, but the underlying regulatory mechanisms remain largely unclear. In this study, we searched for mTOR regulators and found that the splicing factor SRRM2 modulates the levels of S6K1 and S6K2, thereby activating the mTOR-S6K pathway. Interestingly, SRRM2 facilitates the expression of S6K2 by modulating alternative splicing, and enhances the stability of the S6K1 protein by regulating the E3 ubiquitin ligase WWP2. Moreover, SRRM2 is highly expressed in colorectal cancer (CRC) tissues and is associated with a poor prognosis. SRRM2 promotes CRC growth in vitro and in vivo. Combined, these data reveal an oncogenic role of SRRM2 in CRC through activating the mTOR-S6K pathway by two different approaches, further suggesting SRRM2 as a potential therapeutic target for CRC.

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Fig. 1: SRRM2 activates the mTOR-S6K signaling pathway.
Fig. 2: SRRM2 regulates S6K2 splicing.
Fig. 3: SRRM2 enhances S6K1 levels through inhibiting the E3 ligase WWP2.
Fig. 4: WWP2 regulates S6K1 turnover via the ubiquitin-proteasome system.
Fig. 5: SRRM2 promotes colorectal cancer cell growth.
Fig. 6: SRRM2 promotes colorectal tumor growth in vivo.
Fig. 7: SRRM2 promotes colorectal cancer cell growth through the activation of the mTOR-S6K pathway.
Fig. 8: SRRM2 is highly expressed in human CRC and predicts a poor clinical outcome.

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Data availability

The colon cancer patient databases used in this study are available and obtained from UALCAN database and Kaplan-Meier Plotter database. The RNA-seq dataset analyzed in this study is available in the SRA database: no. PRJNA1144892. Additional resources and data related to this article can be found in supplementary information or requested from the corresponding authors.

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Acknowledgements

We are grateful to the members of the Rao laboratory and Drs. H. Hu, F. Rao for discussion. This study was supported by the National Key Research and Development Program (2021YFA0909300), National Natural Science Foundation of China (82170159), Shenzhen Fundamental Research Program (JCYJ20220818100412028), Key Talent Program of Guangdong (2021CX02Y084), High level of special funds (G03050K003), Medical Research Innovation Project (G030410001), China Postdoctoral Science Foundation (2022M721479).

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  1. These authors contributed equally: Zhengwei Yan, Luling He.

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China

    Zhengwei Yan, Luling He, Jiawei Yuan, Yulong Niu, Changzheng Du & Hai Rao

  2. Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China

    Shimin Shuai

  3. School of Medicine, Nanchang University, Nanchang, Jiangxi, China

    Shiwen Luo

  4. Beijing Tsinghua Changgung Hospital & Tsinghua University School of Medicine, 168 Litang Road, Changping District, Beijing, 102218, PR China

    Changzheng Du

  5. Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China

    Hai Rao

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Contributions

ZY and HR designed experiments. ZY and LH performed most of the experiments and analyzed data with HR. CD, JY, and YN performed some of the experiments. SS analyzed thE RNA-Seq data. HR, SL, ZY and LH drafted the manuscript. All authors reviewed and approved the final draft.

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Correspondence to Hai Rao.

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The animal study was reviewed and approved by the laboratory animal ethics committe of SUSTech (SUSTech-SL2023072404). All animal procedures were performed in accordance with the guidelines for care and use of laboratory animals of Southern University of Science and Technology.

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Yan, Z., He, L., Yuan, J. et al. The splicing factor SRRM2 modulates two S6K kinases to promote colorectal cancer growth. Oncogene 44, 1284–1299 (2025). https://doi.org/10.1038/s41388-025-03307-1

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