Feng Qin, Kim Hong, Barua Amrita, Huang Luping, Bolaji Modupeola, Zachariah Sharon, Jung Sung Yun, He Bin, Zhou Tianyi, Mitra Aroshi
University of Houston.
Baylor College of Medicine.
Res Sq. 2023 Feb 22:rs.3.rs-2035901. doi: 10.21203/rs.3.rs-2035901/v1.
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.
前列腺癌是美国男性中最常被诊断出的非皮肤癌。TDRD1是一种生殖细胞特异性基因，在超过一半的前列腺肿瘤中错误表达，但其在前列腺癌发展中的作用仍不清楚。在本研究中，我们鉴定了一个调节前列腺癌细胞增殖的PRMT5-TDRD1信号轴。PRMT5是一种对小核核糖核蛋白（snRNP）生物合成至关重要的蛋白质精氨酸甲基转移酶。PRMT5对Sm蛋白的甲基化是在细胞质中组装snRNPs的关键起始步骤，而snRNP的最终组装在细胞核中的 Cajal 体中进行。通过质谱分析，我们发现TDRD1与snRNP生物合成机制的多个亚基相互作用。在细胞质中，TDRD1以PRMT5依赖的方式与甲基化的Sm蛋白相互作用。在细胞核中，TDRD1与Cajal体的支架蛋白卷曲螺旋蛋白相互作用。前列腺癌细胞中TDRD1的缺失破坏了Cajal体的完整性，影响了snRNP的生物合成，并降低了细胞增殖。综上所述，本研究首次阐述了TDRD1在前列腺癌发展中的功能，并表明TDRD1是前列腺癌治疗的潜在治疗靶点。
