Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G 1 cyclins/cyclin‐dependent kinases and the phosphoinositide 3‐kinase/ AKT signaling cascade

• Published in: Cancer science Vol. 103; no. 9; pp. 1640 - 1650
• Main Authors: Wei, Tong‐You W., Juan, Chi‐Chang, Hisa, Jiun‐Yi, Su, Li‐Jen, Lee, Yuan‐Chii G., Chou, Hsiang‐Yun, Chen, Jo‐Mei M., Wu, Yu‐Chung, Chiu, Shao‐Chih, Hsu, Chung‐Ping, Liu, Kuo‐Lin, Yu, Chang‐Tze R.
• Format: Journal Article
• Language: English
• Published: 01.09.2012
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2012.02367.x

Increasing evidence suggests that PRMT 5, a protein arginine methyltransferase, is involved in tumorigenesis. However, no systematic research has demonstrated the cell‐transforming activity of PRMT 5. We investigated the involvement of PRMT 5 in tumor formation. First, we showed that PRMT 5 was associated with many human cancers, through statistical analysis of microarray data in the NCBI GEO database. Overexpression of ectopic PRMT 5 per se or its specific sh RNA enhanced or reduced cell growth under conditions of normal or low concentrations of serum, low cell density, and poor cell attachment. A stable clone that expressed exogenous PRMT 5 formed tumors in nude mice, which demonstrated that PRMT 5 is a potential oncoprotein. PRMT 5 accelerated cell cycle progression through G 1 phase and modulated regulators of G 1; for example, it upregulated cyclin‐dependent kinase ( CDK ) 4, CDK 6, and cyclins D 1, D 2 and E 1, and inactivated retinoblastoma protein ( R b). Moreover, PRMT 5 activated phosphoinositide 3‐kinase ( PI 3K)/ AKT and suppressed c‐ J un N ‐terminal kinase ( JNK )/c‐ J un signaling cascades. However, only inhibition of PI 3 K activity, and not overexpression of JNK , blocked PRMT 5‐induced cell proliferation. Further analysis of PRMT 5 expression in 64 samples of human lung cancer tissues by microarray and western blot analysis revealed a tight association of PRMT 5 with lung cancer. Knockdown of PRMT 5 retarded cell growth of lung cancer cell lines A 549 and H 1299. In conclusion, to the best of our knowledge, we have characterized the cell‐transforming activity of PRMT 5 and delineated its underlying mechanisms for the first time.