Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, Asahikawa, Japan.
Cell Death Dis. 2020 Apr 17;11(4):245. doi: 10.1038/s41419-020-2439-7.
RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression. However, the tumor-associated functions as well as the detailed mechanisms underlying the anti-tumor effects of most RBPs have yet to be explored. We herein report that the phosphorylated heterogeneous ribonucleoprotein (hnRNP) A0 promotes mitosis through the RAS-associated protein 3 GTPase-activating protein catalytic subunit 1 (RAB3GAP1)-Zeste white 10 interactor (ZWINT1) cascade. The downregulation assay of 20 representative hnRNPs, a major family of RNA-binding proteins, in colorectal cancer cells revealed that hnRNPA0 is a strong regulator of cancer cell growth. The tumor promotive function of hnRNPA0 was confirmed in gastrointestinal cancer cells, including pancreatic, esophageal, and gastric cancer cells, but not in non-cancerous cells. Flow cytometry and Western blotting analyses revealed that hnRNPA0 inhibited the apoptosis through the maintenance of G2/M phase promotion in colorectal cancer cells. A comprehensive analysis of mRNAs regulated by hnRNP A0 and immunostaining revealed that mitotic events were regulated by the hnRNPA0-RAB3GAP1 mRNA-mediated ZWINT-1 stabilization in colorectal cancer cells, but not in non-tumorous cells. The interaction of hnRNP A0 with mRNAs was dramatically changed by the deactivation of its phosphorylation site in cancer cells, but not in non-tumorous cells. Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.
RNA 结合蛋白 (RBP) 介导的 RNA 调控已被证明与维持内稳态以及癌症进展有关。然而，大多数 RBP 的肿瘤相关功能以及其抗肿瘤作用的详细机制尚未被探索。本文报道了磷酸化异质核糖核蛋白 (hnRNP) A0 通过 RAS 相关蛋白 3 GTP 酶激活蛋白催化亚基 1 (RAB3GAP1)-Zeste white 10 相互作用蛋白 (ZWINT1) 级联促进有丝分裂。在结直肠癌细胞中下调 20 种代表性 RBP（RNA 结合蛋白的主要家族）的表达谱，发现 hnRNPA0 是一种强烈的癌细胞生长调控因子。hnRNPA0 的肿瘤促进功能在胃肠道癌细胞（包括胰腺、食管和胃癌细胞）中得到了证实，但在非癌细胞中没有。流式细胞术和 Western blot 分析表明，hnRNPA0 通过维持结直肠癌细胞的 G2/M 期促进来抑制细胞凋亡。对 hnRNP A0 调控的 mRNA 进行综合分析和免疫染色表明，在结直肠癌细胞中，有丝分裂事件受 hnRNPA0-RAB3GAP1 mRNA 介导的 ZWINT-1 稳定调控，而非在非肿瘤细胞中。在癌细胞中，hnRNP A0 与 mRNA 的相互作用由于其磷酸化位点失活而发生显著改变，但在非肿瘤细胞中没有。因此，RBP 异常磷酸化所具有的肿瘤特异性生物学功能被认为是肿瘤治疗的一个有吸引力的靶点。
