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SNHG4-mediated PTEN destabilization confers oxaliplatin resistance in colorectal cancer cells by inhibiting ferroptosis

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Abstract

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance.

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All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed in the study are available from the corresponding author on reasonable request.

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Acknowledgements

Not applicable.

Funding

This study was partially supported by research funding from the National Natural Science Foundation of China (No. 82160446). Guangxi Medical and health key discipline construction project; the Training Program for 1000 Young and Middle-aged Key Teachers in Guangxi.

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Author notes

  1. Si-qi Li, Wen-ting Xu, Yi-xin Yin have contributed equally to this work.

Authors and Affiliations

  1. Department of Research, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, 530021, Guangxi, China

    Si-qi Li, Wen-ting Xu, Yi-xin Yin, Ke-zhi Li, Feng Lv, Li-ye Xie & Bang-li Hu

  2. Department of Gastrointestinal Surgery, Third Affiliated Hospital of Guangxi Medical University, Guangxi, 530031, China

    Hao-tang Wei

  3. Department of Chemotherapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi, China

    Ming-zhi Xie

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  1. Si-qi Li
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Contributions

Study concept and design: LSQ, YYX and HBL; Collection and assembly of data: LSQ, WHT and XLY; Performed the experiment: LSQ, LKZ, XWT, XMZ and LF; Data analysis and interpretation: LSQ, DHW, LKZ and YYX; Manuscript writing and review: All authors. All authors have read and approved the manuscript in its current state.

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Correspondence to Bang-li Hu.

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The authors declare that they have no competing interests.

Ethical approval and consent to participate

This study was approval by the Ethics Committee of Guangxi Medical University Cancer Hospital. The animal experimental procedures in mice were approved by the ethics committee of Animal Experiments of Guangxi Medical University. All the procedures were carried out in accordance with institutional guidelines.

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Li, Sq., Xu, Wt., Yin, Yx. et al. SNHG4-mediated PTEN destabilization confers oxaliplatin resistance in colorectal cancer cells by inhibiting ferroptosis. Apoptosis 29, 835–848 (2024). https://doi.org/10.1007/s10495-024-01948-3

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