Fig. 8: Pharmacological inhibition of PRMT4, 5, and 7 alters RNA alternative splicing and suppresses cancer cell growth. | Nature Communications

Fig. 8: Pharmacological inhibition of PRMT4, 5, and 7 alters RNA alternative splicing and suppresses cancer cell growth.

From: Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth

Fig. 8: Pharmacological inhibition of PRMT4, 5, and 7 alters RNA alternative splicing and suppresses cancer cell growth.

a–c, d, f, h MCF7 (a, d), HCT 116 (b, f), or LNCaP (c, h) cells were treated with EZM2302 (10 μM), GSK591 (10 μM), or SGC3027 (10 μM) alone or in combination (+++) for duration as indicated followed by proliferation assay (a–c) or colony formation assay (d, f, h). n = 3 biological replicates for cell proliferation assay (mean ± SD, **P < 0.01, ***P < 0.001, day 4 by unpaired Student t-test, two-tailed). e, g, i Quantification of the crystal violet dye as shown in (d), (f), and (h). Absorbance was measured three time. j–l MCF7 (j), HCT 116 (k), or LNCaP (l) cells were treated with EZM2302 (10 μM), GSK591 (10 μM), or SGC3027 (10 μM) alone or in combination for 24 h as indicated followed by alternative splicing analysis. n = 2 biological replicates and representative data are shown. m A working model of PRMT4-, 5-, and 7-mediated arginine methylation in alternative splicing regulation and cancer cell growth. Global profiling of PRMT4-, 5-, and 7-mediated arginine methylation revealed that PRMT4-, 5-, and 7-methylome shared a group of proteins with implications in mRNA splicing, and RNA-seq analysis confirmed the global impact of these three PRMTs on gene alternative splicing. Exemplified by hnRNPA1, a critical regulator of gene alternative splicing, PRMT4-, 5-, and 7-mediated arginine methylation was shown to be involved in hnRNPA1 binding with pre-mRNA and, therefore, the regulation of those alternative splicing events commonly regulated by PRMT4, 5, and 7. In cancers, such as breast, colorectal, and prostate cancer, PRMT4, 5, and 7 were found to be overexpressed, leading to elevated levels of arginine methylation on their substrates including hnRNPA1, and therefore aberrant alternative splicing changes, which potentially drive cancer cell growth. Pharmacological inhibition of PRMT4, 5, and 7 exhibited great potential in suppressing the growth of cancer cells. Source data are provided as a Source data file.

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