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A noncanonical E3 ubiquitin ligase RNF41-mediated MYO1C stability promotes prostate cancer metastasis by inducing actin remodeling

Oncogene volume 43, pages 2696–2707 (2024)Cite this article

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Abstract

Prostate cancer bone metastasis is a predominant cause of death for prostate cancer (PCa) patients. However, the underlying mechanisms are poorly understood. Here, we report that high levels of RNF41 are associated with metastatic human prostate cancer. RNF41 silencing inhibits prostate cancer cell growth, cell migration and invasion in vitro and in vivo. Mechanistically, we identify that RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability and induce actin remodeling, which promotes PCa bone metastasis. RNF41 was significantly upregulated in metastatic prostate cancer tissues and positively associated with MYO1C expression. Furthermore, we show in intraarterial injected-bone metastasis xenograft model that targeting MYO1C stability by inhibition of RNF41 markedly suppressed PCa bone metastasis. Collectively, our findings identify RNF41 is an important regulator of prostate cancer cell growth and metastasis and targeting RNF41/MYO1C could be a valuable strategy to ameliorate prostate cancer progression and metastasis.

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Fig. 1: Elevated of RNF41 expression correlates with PCa progression.
Fig. 2: RNF41 silencing reduces PCa cell proliferation, migration and invasion.
Fig. 3: RNF41 directly interacts with and ubiquitinates MYO1C through K27/K63-linked ubiquitination.
Fig. 4: RNF41 protein stabilizes MYO1C and is upregulated in human prostate cancer and positively correlates with MYO1C protein levels.
Fig. 5: RNF41 regulates MYO1C-induced actin remodeling to promote PCa cell migration and invasion.
Fig. 6: RNF41 inhibitors suppress MYO1C-dependent PCa cell migration and invasion in vitro and vivo.

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All data generated or analyzed during this study are included in this published article and supplementary files.

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Acknowledgements

We would like to thank Dr. Jianfei Qi (University of Maryland) for giving us the plasmids of HA-ub (K6R), HA-ub (K11R), HA-ub (K27R), HA-ub (K29R), HA-ub (K33R), HA-ub (K48R) and HA-ub (K63R). This work is supported by the National Natural Science Foundation of P.R. China (Grant No. 82172921), Jiangxi Provincial Natural Science Foundation for Distinguished Young Scholars (Grant No.20232ACB216014), the Natural Science Foundation of Jiangxi (grant no. 20151BAB205047), the National Natural Science Foundation of P.R. China (Grant No. 82260500) and Foundation of Jiangxi Provincial Key Laboratory of Urinary System Diseases (2024SSY06111).

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Author notes

  1. These authors contributed equally: Situ Xiong, Sheng Li.

Authors and Affiliations

  1. Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Situ Xiong, Sheng Li, Zhongqi Li, Lin Yang, Hailang Yang, Jing Xiong, Ju Guo, Bin Fu & Songhui Xu

  2. Department of Quality Control, The First Affiliated Hospital of Nanchang University, Nanchang, China

    Yanping Song

  3. College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China

    Wang Pan

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Contributions

Conceptualization, SHX, JG and BF; methodology, STX, SL and ZQL; investigation, SL and STX; data curation, SL, STX, and ZQL; resources, SL, STX, YQS, JX and WP; writing-original draft, SHX and STX; visualization, SL, STX, JX and WP; supervision, SHX, JG and BF; funding acquisition, SHX, JG and BF.

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Correspondence to Ju Guo, Bin Fu or Songhui Xu.

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Xiong, S., Li, S., Li, Z. et al. A noncanonical E3 ubiquitin ligase RNF41-mediated MYO1C stability promotes prostate cancer metastasis by inducing actin remodeling. Oncogene 43, 2696–2707 (2024). https://doi.org/10.1038/s41388-024-03120-2

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