Shen Yao, Zhao Pan, Dong Kewei, Wang Jiajia, Li Huichen, Li Mengyang, Li Ruikai, Chen Suning, Shen Yuxia, Liu Zhiyu, Xie Mianjiao, Shen Peng, Zhang Jian
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.
The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
Cancer Metab. 2022 Dec 6;10(1):22. doi: 10.1186/s40170-022-00299-4.
Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood.
We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified.
PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo.
Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.
蛋白质精氨酸甲基转移酶5（PRMT5）在多种肿瘤中上调，并在癌细胞增殖中起关键作用。然而，PRMT5在结直肠癌中的作用仍知之甚少。
我们使用在线数据库以及通过免疫组织化学染色、定量实时聚合酶链反应（qRT-PCR）和蛋白质印迹法检测PRMT5和糖酵解酶在结直肠癌细胞系中的表达水平。并进行MTT和集落形成试验以研究细胞增殖。然后，我们使用生物能量分析仪评估细胞外酸化率（ECAR）和氧消耗率（OCR）水平，以研究结直肠癌的能量状态，并通过双荧光素酶报告基因试验和染色质免疫沉淀试验检测转录调控。最后，验证了他达拉非和5-氟尿嘧啶联合治疗的疗效。
与正常组织相比，PRMT5在结直肠癌组织中高表达，且与CRC患者的不良预后相关。然后，我们证明PRMT5基因敲低或功能丧失会减弱CRC细胞的活力，而PRMT5的过表达则促进细胞增殖。机制上，PRMT5通过转录激活LDHA表达增强糖酵解。此外，PRMT5抑制剂他达拉非在体外和体内均使CRC细胞对抗肿瘤药物5-氟尿嘧啶敏感。
我们的数据表明，PRMT5部分通过激活糖酵解促进结直肠癌增殖，可能是结直肠癌治疗的潜在靶点。
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