RIO Kinase 1 (RIOK1) is involved in various pathologies, including cancer. However, the role of RIOK1 in radioresistance of colorectal cancer (CRC) remains largely unknown. In this study, we reported that RIOK1 was overexpressed in rectal cancer tissue with weaker tumor regression after neoadjuvant chemoradiotherapy (neoCRT). Moreover, higher RIOK1 expression predicted a poor prognosis in patients with rectal cancer. Blockade of RIOK1 using Toyocamycin, a pharmacological inhibitor of RIOK1, or by knocking down its expression, decreased the resistance of CRC cells to radiotherapy in vitro and in vivo. A mechanistic study revealed that RIOK1 regulates radioresistance by suppressing the p53 signaling pathway. Furthermore, we found that RIOK1 and Ras-GAP SH3 domain binding protein 2 (G3BP2) interact with each other. RIOK1 phosphorylates G3BP2 at Thr226, which increases the activity of G3BP2. RIOK1-mediated phosphorylation of G3BP2 facilitated ubiquitination of p53 by murine double minute 2 protein (MDM2). Altogether, our study revealed the clinical significance of RIOK1 in CRC, and therapies targeting RIOK1 might alleviate the CRC tumor burden in patients.
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The RNA-seq datasets analyzed for this study are available in the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/sra/). BioProject accession number: PRJNA827462.
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This work was supported by China Postdoctoral Science Foundation (No. 2019M663289), Natural Science Foundation of Guangdong Province (Nos. 2019A1515110144 and 2021A1515111014) and National Natural Science Foundation of China (No. 81572725).
The authors declare no competing interests.
Ethics approval and consent to participate
Approvals from the ethical committee of Sun Yat-sen University Cancer Center and prior patient’s consents were previously obtained for the use of these clinical specimens for research purpose. The animal experiments were conducted according to the Animal Study Guidelines of the Ethics Committee of Sun Yat-sen University.
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Chen, Y., Zhou, S., Wan, K. et al. RIOK1 mediates p53 degradation and radioresistance in colorectal cancer through phosphorylation of G3BP2. Oncogene 41, 3433–3444 (2022). https://doi.org/10.1038/s41388-022-02352-4