USP46 inhibits cell proliferation in lung cancer through PHLPP1/AKT pathway

Abstract

Background: USP46 has been shown to function as tumor suppressor in colon cancer and renal cell carcinoma. However, its specific role in other cancers remains unknown. This study was aimed to investigate the role of USP46 in lung cancer tumorigenesis, and to identify the underlying mechanism. Methods: 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 lung cancer patients. The functional role of USP46 in regulating proliferation in lung cancer cells were examined by cell proliferation assay, radiation assay, genetic overexpression and knock down and chemical inhibition of relevant genes. The underlying mechanisms were investigated in multiple lung cancer cell line models by co-immunoprecipitation and ubiquitination assays. Results: This study identified strong downregulation of USP46 and PHLPP1 expression in lung cancer tissues relative to normal adjacent tissues. USP46 was further shown to inhibit lung cancer cell proliferation under normal growth conditions and during radiation induced DNA damage by antagonizing the ubiquitination of PHLPP1 resulting in the inhibition of AKT signaling. The effect of USP46 knock down on lung cancer cell proliferation was significantly reversed by exposure to radiation and AKT inhibition. Conclusions: USP46 is down-regulated in lung cancer, and it suppresses proliferation of lung cancer cells by inhibiting PHLPP1/AKT pathway. AKT inhibition slows proliferation of USP46 down-regulated lung cancer cells exposed to radiation suggesting a potential therapeutic avenue for USP46 down-regulated lung cancer through a combination of radiation and AKT inhibitor treatment.

MiR‐27a‐3p targets USP46 to inhibit the cell proliferation of hepatocellular carcinoma

“…In colorectal cancer, renal cell carcinoma, and lung cancer, USP46 has been confirmed to be abnormally down‐regulated. As a tumor suppressor gene, it can antagonize the activity of AKT by deubiquitinating the PH domain leucine‐rich repeat protein phosphatase 1 (PHLPP1), thereby inhibiting the proliferation of cancer cells (Gui et al, 2019; Li et al, 2013; Wang et al, 2020). In esophageal squamous cell carcinoma, Tian et al confirmed the over‐expression of USP46 by analyzing clinical samples, and in vitro studies confirmed that USP46 enhances the migration and invasion of esophageal squamous cell carcinoma cells by mediating the EMT process (Tian et al, 2020).…”

Ubiquitin specific protease 46 potentiates triple negative breast cancer development by stabilizing PGAM1‐mediated glycolysis

“…USP46 stablization of PHLPP reduced AKT activity and led to suppressed tumor growth of colon cancer cells (Li et al, 2013, Wen et al, 2013). USP46 also negatively regulated PHLPP/AKT signaling axis and suppressed cancer cell function in renal cell carcinoma and lung cancer (Gui et al, 2019, Wang et al, 2020). Oppositely, USP46 was shown to participate in high‐risk human papilloma viruses (HPVs) replication (Lehoux et al, 2014).…”