Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673.
Nucleic Acids Res. 2012 Oct;40(19):9534-42. doi: 10.1093/nar/gks858. Epub 2012 Sep 16.
p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.
p21 是一种有效的细胞周期蛋白依赖性激酶抑制剂，在促进 G1 细胞周期阻滞和细胞衰老中发挥作用。与这一作用一致，p21 是几种肿瘤抑制因子和癌基因的下游靶标，并且在包括乳腺癌在内的大多数肿瘤中下调。在这里，我们报告蛋白精氨酸甲基转移酶 6（PRMT6），一种已知作为转录共因子起作用的 I 型 PRMT，直接抑制 p21 启动子。PRMT6 敲低（KD）导致乳腺癌细胞中 p21 的去抑制，这是 p53 非依赖性的，并导致细胞周期阻滞、细胞衰老和在软琼脂测定以及所有检查的癌症系的严重联合免疫缺陷（SCID）小鼠中生长减少。我们最后表明，绕过 p21 介导的阻滞可使 PRMT6 KD 细胞免于衰老，并恢复它们在软琼脂上生长的能力。我们得出结论，PRMT6 在乳腺癌细胞中作为癌基因发挥作用，促进生长并防止衰老，使其成为癌症治疗的有吸引力的靶标。
