USP46 Inhibits Cell Proliferation in Lung Cancer through PHLPP1/AKT Pathway.

Wei Wang,Meng Chen,Hailing Xu,Dongqing Lv,Haihua Yang,Suna Zhou

doi:10.1155/2020/2509529

Abstract

Previous studies have shown that ubiquitin-specific protease 46 (USP46) is a tumor suppressor in colon cancer and renal cell carcinoma. However, its specific role in other cancers is still poorly understood. This study is aimed at investigating the role of USP46 in lung cancer tumorigenesis and identifying its underlying mechanisms. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were used to measure the expression levels of USP46 and PHLPP1 in lung cancer tissue and adjacent normal tissue from patients with lung cancer. We examined the ability of USP46 to regulate cell proliferation in lung cancer cells via cell proliferation assay, radiation assay, genetic overexpression and knockdown, and chemical inhibition of relevant genes. We investigated the underlying mechanisms in multiple lung cancer cell line models by coimmunoprecipitation and ubiquitination assays. In this study, we identified a strong downregulation of the expressions of USP46 and PHLPP1 in lung cancer tissues relative to normal adjacent tissues. USP46 was further shown to inhibit lung cancer cell proliferation under conditions of normal growth and during radiation-induced DNA damage by antagonizing the ubiquitination of PHLPP1 resulting in the inhibition of AKT signaling. Exposure to radiation and AKT inhibition significantly reversed the effect of USP46 siRNA on lung cancer cell proliferation. USP46 is downregulated in lung cancer and suppresses the proliferation of lung cancer cells by inhibiting the PHLPP1/AKT pathway. AKT inhibition slows the proliferation of lung cancer cells that have been downregulated by USP46 and exposed to radiation. This suggests a potential therapeutic avenue for USP46-downregulated lung cancer through a combination of radiation and AKT inhibitor treatment.

Highlights

Lung cancer is the most deadly form of cancer for the sexes and has one of the worst survival rates [1]
We found that cancer tissues had significantly lower levels of Ubiquitin-specific protease 46 (USP46) messenger RNA (Figure 1(a))
We compared the expression of USP46 in several human lung cancer cell lines to normal human bronchial epithelial (HBE) cells and found that USP46 expression was greatly decreased both in messenger RNA (mRNA) levels (Figure S1A) and protein levels (Figure S1B) in the lung cancer cell lines compared to HBE cells

Summary

Introduction

Lung cancer is the most deadly form of cancer for the sexes and has one of the worst survival rates [1]. About 1.6 million people are estimated to die from lung cancer [2]. Recent advancements in cancer therapies have improved the survival rate of patients with lung cancer; there are still unmet needs in terms of therapies. A key step toward developing effective therapies against lung cancer is elucidating the molecular mechanisms underlying tumorigenesis. Protein posttranslational modifications play important roles in regulating numerous biological processes, such as the cell cycle, DNA damage repair, and apoptosis [3]. Ubiquitination is one of the most ubiquitous posttranslational modifications and is dynamically regulated by ubiquitin ligases and deubiquitinase [4].

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