MicroRNA-101-3p Suppresses Cancer Cell Growth by Inhibiting the USP47-Induced Deubiquitination of RPL11.

Jinyoung Park,Jinhong Cho,Moonsoo Cho,Eunice Eunkyeong Kim,Eun Joo Song

doi:10.3390/cancers14040964

Abstract

Simple SummaryAn abnormal expression of microRNA is commonly observed in cancer. Since a single miRNA can target numerous genes, it is important to understand the exact mechanism for the regulation of cancer growth by miRNAs. Here, we show that miR-101-3p, which is downregulated in several cancers, regulates RPL11 ubiquitination by targeting USP47, thereby controlling p53 levels by affecting the localization of RPL11 and its interaction with MDM2. Our results provide a novel mechanism for the inhibition of cancer cell growth by miR-101-3p, and suggest that miR-101-3p could be a potential target as an anticancer agent.MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate a countless number of genes in the cell, and the aberrant expression of miRNA can lead to cancer. Here, we demonstrate that miR-101-3p regulates the RPL11–MDM2–p53 pathway by targeting ubiquitin-specific peptidase 47 (USP47), consequently inhibiting cancer cell proliferation. We confirm that miR-101-3p directly binds to the 3′-UTR region of the USP47 gene and inhibits USP47 expression. In addition, the overexpression of miR-101-3p suppresses cell proliferation in a p53-dependent manner. MiR-101-3p promotes interaction between RPL11 and MDM2 by inducing the translocation of RPL11 from the nucleolus to the nucleoplasm, thus preventing the MDM2-mediated proteasomal degradation of p53. However, these phenomena are restored by the overexpression of USP47, but not by its catalytically inactive form. Indeed, miR-101-3p regulates RPL11 localization and its interaction with MDM2 by inhibiting the USP47-induced deubiquitination of RPL11. Finally, the expression of miR-101-3p is downregulated in lung cancer patients, and the patients with low miR-101-3p expression exhibit a lower survival rate, indicating that miR-101-3p is associated with tumorigenesis. Together, our findings suggest that miR-101-3p functions as a tumor suppressor by targeting USP47 and could be a potential therapeutic target for cancers.

Highlights

MicroRNAs are a class of small single-stranded RNA molecules containing approximately 21 to 25 nucleotides with no protein-coding sequences [1,2]
MiR-101-3p has been found to participate in multiple cancer-related biological processes, including proliferation, apoptosis, invasion, and metastasis. It serves as a tumor suppressor in diverse malignancies by targeting critical oncogenes or antioncogenes, including EZH2 [21], DNMT3a [19], MALAT-1 [20], ZEB1 [23], and ubiquitinspecific peptidase 47 (USP47) [24]
Levin and his colleagues showed that miR-101-3p suppresses cancer progression via p53 accumulation by targeting the proteasome maturation protein (POMP), which is involved in the biogenesis of proteasomes [22]

Summary

Introduction

MicroRNAs (miRNAs) are a class of small single-stranded RNA molecules containing approximately 21 to 25 nucleotides with no protein-coding sequences [1,2]. Mature miRNA has a seed sequence that binds to the 3 UTR region of a target mRNA sequence, thereby regulating the levels and functions of a target gene [3,4]. Studies have shown that miRNAs regulate cellular processes, including cell proliferation, apoptosis, and development, and that the dysregulation of miRNAs is associated with many types of diseases, including cancers [5]. MiR-15a and miR-16-1 are mutated or decreased in expression in leukemia, which has been found to be associated with tumorigenesis, and they induce apoptosis by targeting an anti-apoptotic protein, Bcl-2, in many solid malignancies [6,7,8]. High miR-21/miR-29a expression results in the progression of metastasis by directly binding to Toll-like receptor 7 (TLR7) or TLR8, and promoting TLR-mediated prometastatic inflammatory responses [9]

Methods

Results

Conclusion