Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis.

Yang Liu,Yong Zhao,Qiang Chi,Chunyan Yang,Boshi Sun,Zhen Wang

doi:10.18632/aging.102575

Abstract

Methyltransferase-like 1 (METTL1) mediated 7-methylguanosine (m7G) is crucial for the regulation of chemoresistance in cancer treatment. However, the role of METTL1 in regulating chemoresistance of colon cancer (CC) cells to cisplatin is still unclear. This study established the cisplatin-resistant CC (CR-CC) cells and found that METTL1 was low-expressed in CR-CC cells compared to their paired cisplatin-sensitive CC (CS-CC) cells. Besides, overexpressed METTL1 enhanced the cytotoxic effects of cisplatin on CR-CC cells. In addition, miR-149-3p was the downstream target of METTL1, which could be positively regulated by METTL1. Further results validated that miR-149-3p was low-expressed in CR-CC cells comparing to the CS-CC cells. In addition, the promoting effects of overexpressed METTL1 on cisplatin induced CR-CC cell death were abrogated by synergistically knocking down miR-149-3p. Furthermore, S100A4/p53 axis was the downstream target of METTL1 and miR-149-3p, and either overexpressed METTL1 or miR-149-3p increased p53 protein levels in CR-CC cells, which were reversed by upregulating S100A4. Similarly, the promoting effects of overexpressed METTL1 on cisplatin-induced CR-CC cell death were abrogated by overexpressing S100A4. Taken together, overexpression of METTL1 sensitized CR-CC cells to cisplatin by modulating miR-149-3p/S100A4/p53 axis.

Highlights

Cisplatin was the first-line chemotherapeutic drug for colon cancer (CC) treatment in clinic [1, 2]
Previous studies proved that microRNAs could be regulated by Methyltransferase-like 1 (METTL1) in a m7G dependent manner [22], and miR-149-3p was the potential downstream target of METTL1 [10], but the role of METTL1/miR149-3p axis in regulating CC cell functions are still unclear
Further results showed that both METTL1 mRNA (Figure 1F) and miR-149-3p (Figure 1E) were lowly expressed in cisplatin-resistant CC (CR-CC) cells comparing to their paried CSCC cells, and the Western Blot results validated that the expression levels of METTL1 were lower in CR-CC cells comparing to the cisplatin-sensitive CC (CS-CC) cells (Figure 1G–1H)

Summary

Introduction

Cisplatin was the first-line chemotherapeutic drug for colon cancer (CC) treatment in clinic [1, 2]. Methyltransferase-like 1 (METTL1) was crucial for RNA processing (splicing, stability and localization) in a 7methylguanosine (m7G) dependent manner [6,7,8], which served as a tumor suppressor and participated in the development of multiple cancers [9, 10]. Recent studies have identified miR149-3p as a tumor suppressor in multiple cancers, such as prostate cancer [14, 15], pancreatic cancer [16], colon cancer [17] and so on. Previous studies proved that microRNAs could be regulated by METTL1 in a m7G dependent manner [22], and miR-149-3p was the potential downstream target of METTL1 [10], but the role of METTL1/miR149-3p axis in regulating CC cell functions are still unclear

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Conclusion