Abstract
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.
Highlights
Cancer is one of the most frequent causes of death worldwide[1]
Tumor-associated heterogeneous ribonucleoprotein (hnRNP) were screened First, to identify the most important hnRNP affecting colon cancer progression, 20 representative hnRNPs were knocked down in colon cancer HCT116 cells using the siRNAs of each hnRNP (Supplementary Table 1)[22], and cytotoxicity was determined by the sulforhodamine B (SRB) assay
The present study showed that the cancer-specific phosphorylation of heterogeneous ribonucleoprotein A0 maintains tumor mitotic events through the RAB3GAP1-mediated stabilization of ZWINT1
Summary
Cancer is one of the most frequent causes of death worldwide[1]. the development of anti-tumor chemotherapeutic reagents and molecular-targeted drugs has improved the survival rate of cancer patients, current chemotherapy frequently brings adverse events because the targets of current anti-tumor drugs are expressed in non-tumorous cells as well as tumor cells. Cancerspecific alterations that strongly promote the growth of tumors have been explored as targets of cancer therapy. No anti-tumor drug targeting RBPs has yet been established because most RBPs are considered essential for maintaining homeostasis in normal tissues[10,11,12], some RBPs are highly expressed in tumor cells compared with normal cells[13,14]. To resolve this issue, the cancerspecific modifications of RBPs that possess strong
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