Abstract
Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. TDRD1, a germ cell-specific gene, is erroneously expressed in more than half of prostate tumors, but its role in prostate cancer development remains elusive. In this study, we identified a PRMT5-TDRD1 signaling axis that regulates the proliferation of prostate cancer cells. PRMT5 is a protein arginine methyltransferase essential for small nuclear ribonucleoprotein (snRNP) biogenesis. Methylation of Sm proteins by PRMT5 is a critical initiation step for assembling snRNPs in the cytoplasm, and the final snRNP assembly takes place in Cajal bodies in the nucleus. By mass spectrum analysis, we found that TDRD1 interacts with multiple subunits of the snRNP biogenesis machinery. In the cytoplasm, TDRD1 interacts with methylated Sm proteins in a PRMT5-dependent manner. In the nucleus, TDRD1 interacts with Coilin, the scaffold protein of Cajal bodies. Ablation of TDRD1 in prostate cancer cells disrupted the integrity of Cajal bodies, affected the snRNP biogenesis, and reduced cell proliferation. Taken together, this study represents the first characterization of TDRD1 functions in prostate cancer development and suggests TDRD1 as a potential therapeutic target for prostate cancer treatment.
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All data generated or analyzed during this study are included in this published article, Supplementary Information, or in the figshare repository with the https://doi.org/10.6084/m9.figshare.21986486.
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Acknowledgements
This work was supported by the NIH (R01CA211861 to BH, R33AI122418 and R33AI133697 to QF, and S10OD026827-01A1 to BBIC core at the University of Houston).
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QF and BH conceptualized the project. QF and HK planned and designed the project. HK, AB, LH, TZ, MB, SZ and AM performed the experiments. SYJ performed mass spectrum. QF, HK and BH wrote the manuscript. All other authors helped in the discussion and revision of the manuscript.
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The mouse experiments were performed under the protocol (AUP-0121-0002) approved by IACUC at the Houston Methodist Research Institute and protocol (PROTO202000026) approved by IACUC at the University of Houston.
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Kim, H., Barua, A., Huang, L. et al. The cancer testis antigen TDRD1 regulates prostate cancer proliferation by associating with the snRNP biogenesis machinery. Oncogene 42, 1821–1831 (2023). https://doi.org/10.1038/s41388-023-02690-x
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DOI: https://doi.org/10.1038/s41388-023-02690-x
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