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hMTR4 promotes p53 protein degradation and tumor growth by accelerating rRNA processing and regulating the RPL5-MDM2 axis

Cell Death & Differentiation (2025)Cite this article

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Abstract

hMTR4 is an RNA helicase and an essential co-factor for the nuclear RNA exosome. Its role in the p53 pathway and cell cycle control remains unknown. Here, gain- and loss-of-function analyses in cell models showed that hMTR4 could not affect p53 mRNA levels, but decreased the levels of p53 protein and its downstream target genes by promoting p53 ubiquitination and degradation, thus accelerating cell cycle progression. These effects of hMTR4 were abrogated by nutlin-3A, an inhibitor of E3 ligase MDM2. Mechanistically, hMTR4 promoted rRNA processing in an RNA helicase-dependent manner, thus increased the amount of mature rRNA to bind ribosomal protein L5 (RPL5), resulted in sequestration of RPL5 in the nucleolus and reduced binding of RPL5 to MDM2 in the nucleoplasm, consequently promoted MDM2-mediated degradation of p53 protein. Silencing RPL5 blocked the effect of hMTR4 knockdown in upregulating p53, while hMTR4 overexpression abrogated the role of RPL5 in stimulating p53 activity. Interestingly, hMTR4 reduced the mRNA levels of p53-target genes via repressing p53 activity rather than promoting their RNA degradation. These findings disclose a novel hMTR4-rRNA-RPL5-MDM2-p53 axis and highlight hMTR4 and rRNA processing as important regulators of the p53 pathway. Further investigations on clinical samples showed that hMTR4 and RPL5 were frequently upregulated in different malignancies, including hepatocellular carcinoma (HCC), and they exhibited a positive correlation. High hMTR4 level was correlated with high recurrence of HCC, among patients with high RPL5 levels and wildtype p53 in tumors. Studies using mouse xenograft models revealed that silencing Skiv2l2 (the homologue of human hMTR4) in mouse hepatoma cells inhibited xenograft development, and tumor growth was suppressed by intratumoral injection of antisense oligonucleotides (ASO) targeting Skiv2l2. These data suggest the significance of hMTR4 overexpression in promoting tumor growth and its potential as a therapeutic target.

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Fig. 1: hMTR4 downregulates p53 in a helicase activity-dependent manner.
Fig. 2: hMTR4 promotes MDM2-dependent degradation of p53 protein.
Fig. 3: hMTR4 reduces p53 protein level by promoting rRNA processing and MDM2 activity.
Fig. 4: hMTR4 reduces the mRNA levels of p53-target genes via repressing p53 activity rather than promoting RNA degradation.
Fig. 5: hMTR4 promotes cell cycle progression via regulating the MDM2-p53 axis.
Fig. 6: Silencing of hMTR4 suppresses tumor growth via upregulating p53.
Fig. 7: Elevation of hMTR4 is associated with high recurrence of tumors with high RPL5 level and wildtype p53.
Fig. 8: The working model illustrating the regulatory role of hMTR4.

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Data availability

This study did not generate any unique datasets or codes. The data generated in this study are available within the article and its Supplementary data files.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2022YFA1303302 to SMZ); National Natural Science Foundation of China (82230093 and 81930076 to SMZ, 32000494 and 32370773 to CX); Guangdong Basic and Applied Basic Research Foundation (2023A1515012478 to SMZ, 2023A1515012301 to CX); Guangzhou Basic Research project (2023A04J1753 to CX). We thank Prof. Hong Cheng at Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences for providing hMTR4-expressing plasmids and technical assistance, Prof. Yun-Fei Yuan at Sun Yat-sen University Cancer Center for providing human HCC tissues and clinical information, Dr. Yi-Fang Lin and Mr. Yu-Chen Ji for technical assistance.

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Author notes

  1. These authors contributed equally: Chen Xie, Xin-Ling Liang.

Authors and Affiliations

  1. MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Oncology in South China, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China

    Chen Xie, Xin-Ling Liang, Bin Chen, Sui Chen, Fang-Xin Xiong, Qi-Cheng Wang, Zhan-Li Chen, Feng-Jun He & Shi-Mei Zhuang

  2. Guangdong Provincial Key Laboratory of Digestive Cancer Research, Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, PR China

    Yihang Pan & Shi-Mei Zhuang

  3. School of Medicine, Sun Yat-Sen University, Shenzhen, PR China

    Yihang Pan

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Contributions

Conception and design: CX and SMZ; Development of methodology: CX, XLL, and BC; Acquisition of data: CX, XLL, BC, SC, FXX, QCW, ZLC, and FJH; Funding acquisition: CX and SMZ; Data analysis and interpretation: CX, XLL, BC, SC, FXX, QCW, ZLC, FJH, YP, and SMZ; Figure preparation: CX and XLL; Writing the manuscript: CX, XLL, and SMZ; Study supervision: SMZ.

Corresponding authors

Correspondence to Chen Xie or Shi-Mei Zhuang.

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All experiments using human samples were approved by the Institutional Research Ethics Committee at Sun Yat-sen University (Approval number: GZR2020-048) and complied with all relevant ethical guidelines. Informed consent was obtained from each patient. All mouse experiments were approved by the Institutional Animal Care and Use Committee at Sun Yat-sen University (Approval number: SYSU-IACUC-2020-B0621) and complied with all relevant ethical guidelines.

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Xie, C., Liang, XL., Chen, B. et al. hMTR4 promotes p53 protein degradation and tumor growth by accelerating rRNA processing and regulating the RPL5-MDM2 axis. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01541-4

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