The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression.
The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression.
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DOI：
10.1186/s12943-022-01598-6
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发表时间：
2022-05-27
期刊：
影响因子：
37.3
通讯作者：
Feng, Ninghan
中科院分区：
文献类型：
--
作者：
Yao, Bing;Zhu, Sha;Wei, Xiyi;Chen, Ming-Kun;Feng, Yangkun;Li, Zhimin;Xu, Xinyu;Zhang, Yuwei;Wang, Yang;Zhou, Jingwan;Tang, Ningyuan;Ji, Chengjian;Jiang, Peng;Zhao, Shan-Chao;Qin, Chao;Feng, Ninghan
前列腺癌（PCa）是男性中最常见的恶性肿瘤，其机制仍知之甚少。因此，迫切需要发现潜在的新的诊断生物标志物和治疗靶点，从而可能促进有效抗癌策略的发展。通过一系列的体内外功能实验来评价PCa细胞的生物学行为。应用RNA下拉、蛋白质印迹、荧光素酶报告基因、免疫组织化学和染色质免疫沉淀试验来剖析详细的潜在机制。进行高通量测序以筛选PCa和邻近正常组织中差异表达的circRNA。蛋白质精氨酸甲基转移酶5（PRMT 5）的上调与PCa中的不良无进展生存期和多种信号通路的激活相关。PRMT 5通过在CAMK 2N 1的近端启动子区沉积抑制性组蛋白标记H4 R3 me 2s和H3 R8 me 2s来抑制CAMK 2N 1的转录，并在体外和体内导致PCa的恶性进展。此外，发现通过RNA-seq鉴定的PCa组织中的候选circRNA circSPON 2的表达与PCa患者的不良临床结局相关。进一步的结果表明，circSPON 2诱导PCa细胞增殖和迁移，并且circSPON 2诱导的作用被miR-331- 3 p抵消。具体而言，circSPON 2作为miR-331- 3 p的竞争性内源RNA（ceRNA）来减弱miR-331- 3 p对其下游靶PRMT 5的抑制作用。我们的研究结果表明，表观遗传调节因子PRMT 5通过抑制CAMK 2N 1的转录来延缓PCa的进展，并受到circSPON 2/miR-331- 3 p轴的调节，这可能成为侵袭性PCa患者的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s12943-022-01598-6获得。
Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa. The online version contains supplementary material available at 10.1186/s12943-022-01598-6.
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影响因子：
--
作者：
Epis MR;Giles KM;Beveridge DJ;Richardson KL;Candy PA;Stuart LM;Bentel J;Cohen RJ;Leedman PJ
通讯作者：
Leedman PJ
影响因子：
14.9
作者：
Girardot M;Hirasawa R;Kacem S;Fritsch L;Pontis J;Kota SK;Filipponi D;Fabbrizio E;Sardet C;Lohmann F;Kadam S;Ait-Si-Ali S;Feil R
通讯作者：
Feil R
影响因子：
28.5
作者：
Dong Y;He D;Peng Z;Peng W;Shi W;Wang J;Li B;Zhang C;Duan C
通讯作者：
Duan C
影响因子：
14.9
作者：
Liu, Fan;Xu, Ye;Nimer, Stephen D.
通讯作者：
Nimer, Stephen D.
影响因子：
4.8
作者：
COCQUERELLE, C;MASCREZ, B;BAILLEUL, B
通讯作者：
BAILLEUL, B