Abstract
N6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.
Highlights
Colorectal cancer, a widespread malignant tumor, is the third most frequent cancer and one of the leading causes of cancer-related death globally [1]
The expression of KIAA1429 is increased in human colorectal cancer cells KIAA1429 was shown to play important role in various cancers, including gastric cancer, lung cancer, and hepatocellular carcinoma
The results indicated that KIAA1429 was highly expressed in colorectal cancer cells compared with normal colon mucosal epithelial cells (Fig. 2C, D)
Summary
Colorectal cancer, a widespread malignant tumor, is the third most frequent cancer and one of the leading causes of cancer-related death globally [1]. Despite advances in therapeutic methods, such as surgical resection combined with chemotherapy and radiotherapy, the progress in colorectal cancer treatment remains sluggish. 40–50% of newly diagnosed patients developed metastatic tumors, and small fraction of these patients can undergo curative resection and the overall survival of the patients with metastatic tumors reaches only 30 months [2]. Surgery and radiotherapy are widely used in clinics. It has been identified that both surgery and radiotherapy triggered undesirable metastasis in certain cases, which limits their use [3,4,5,6,7]. Chemotherapy drugs are widely used based on their inhibitory effect on the growth and induction of apoptosis in cancer cells. Numerous studies are attempting to investigate the underlying mechanism and develop novel therapeutic targets to improve the therapy
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