The protein arginine methyltransferase 6 (PRMT6) is a coregulator of gene expression by methylation of the histone H3 on arginine 2 (H3R2), H4R3 and H2AR3 [1,2]. PRMT6 is aberrantly expressed in various types of human cancer, and abnormal methylation in cancers caused by overexpression of PRMT6 is considered to correlate with poor recovery prognosis [3,4]. However, mechanisms that regulate PRMT6 protein stability in cells remain largely unknown. Here we identified that an orphan F-box protein, FBXO24, that binds to 270 to 275 amino acid residues of PRMT6 to cause polyubiquitination of lysine at position 369 of PRMT6, which mediates its degradation via the ubiquitin-proteasome pathway. Overexpression of FBXO24 or knockout of PRMT6 was found to inhibit cell proliferation, migration, and invasion in H1299 cells. PRMT6 K369R mutant became resistant to degradation. Overexpression of PRMT6 K369R caused cell cycle progression, resulting in cell proliferation. Thus, our data confirm that FBXO24 regulates cell proliferation by mediating ubiquitin-dependent proteasomal degradation of PRMT6.

蛋白质精氨酸甲基转移酶6（PRMT6）通过精氨酸2（H3R2），H4R3和H2AR3上的组蛋白H3甲基化而成为基因表达的共调节子[1,2]。PRMT6在各种类型的人类癌症中异常表达，并且PRMT6的过表达引起的癌症中的异常甲基化被认为与不良的预后相关[3,4]。然而，调节PRMT6蛋白在细胞中稳定性的机制仍然未知。在这里，我们确定了一个孤立的F-box蛋白FBXO24，它与PRMT6的270至275个氨基酸残基结合，导致PRMT6 369位赖氨酸的多泛素化，该蛋白通过泛素-蛋白酶体途径介导其降解。发现FBXO24的过表达或PRMT6的敲除可抑制H1299细胞中的细胞增殖，迁移和侵袭。PRMT6 K369R突变体变得耐降解。PRMT6 K369R的过表达引起细胞周期进程，导致细胞增殖。因此，我们的数据证实FBXO24通过介导PRMT6的泛素依赖性蛋白酶体降解来调节细胞增殖。