Ubiquitin-specific peptidase 46 (USP46) suppresses renal cell carcinoma tumorigenesis through AKT pathway inactivation

Gui, Dingwen; Peng, Wei; Jiang, Weidong; Huang, Geng; Liu, Gang; Ye, Zhihua; Wang, Yang; Xu, Zuwei; Fu, Jinlun; Luo, Shuai; Zhao, Yunfei

doi:10.1016/j.bbrc.2019.09.036

Cited by 12 publications

(10 citation statements)

References 19 publications

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“…In this study, we showed that USP46 expression is downregulated in patients with lung cancer, suggesting a tumor suppressor role of USP46 in lung cancer, which is consistent with the reports from other studies in colorectal cancer [ 9 ] and renal cell carcinoma [ 13 ]. Functionally, we demonstrated that USP46 inhibits cell proliferation in lung cancer cells under normal growth conditions and in cells exposed to IR.…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with the antiproliferation activity of USP46, the protein was found to be downregulated in colorectal cancer [ 9 ], suggesting that USP46 is an important tumor suppressor gene. USP46 has equally shown a tumor suppressor activity in renal cell carcinoma with a similar mechanism to that described in colorectal cancer [ 13 ]. However, the detailed relationship between USP46 and the PHLPP1/AKT pathway is still less investigated in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Chen

et al. 2020

BioMed Research International

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Wang

Chen

et al. 2020

BioMed Research International

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“…In this study, we showed that USP46 expression is downregulated in lung cancer patients, suggesting a tumor suppressor role of USP46 in lung cancer, which is consistent with the reports from other studies in colorectal cancer [7] and renal cell carcinoma [11]. Functionally, we demonstrated USP46 inhibits cell proliferation in lung cancer cells under normal growth conditions as well as in cells exposed to ionizing radiation.…”

Section: Discussionsupporting

confidence: 91%

“…Consistent with the anti-proliferation activity of USP46, the protein is found to be down-regulated in colorectal cancer [7], suggesting that USP46 is an important tumor suppressor gene. The tumor suppressor activity of USP46 has been shown in renal cell carcinoma as well with a similar mechanism as described in colorectal cancer [11]. The role of USP46 in other cancers remains unclear.…”

Section: Introductionmentioning

confidence: 61%

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

Wang

Chen

et al. 2020

Preprint

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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.

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“…One of the genes here was the Ubiquitin Specific Peptidase 46 (USP46) gene. This is a protein coding gene which belongs to a large gene family of cysteine proteases that function as deubiquitinating enzymes (DUBs), and has been associated with maternal behavior in mice [58], mastitis resistance in sows [59], and breast cancer in humans [60]. DUBs may regulate gamma-Aminobutyric acid (GABA) action which is an inhibitory neurotransmitter but can also suppress inflammatory immune response while promoting regulatory immune response.…”

Section: Plos Onementioning

confidence: 99%

Genome-wide association study for mammary structure in Canadian Angus cows

et al. 2020

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Functional and enduring mammary structure is pivotal for producer profitability, and animal health and welfare in beef production. Genetic evaluations for teat and udder score in Canadian Angus cattle have previously been developed. The aim of this study was to identify genomic regions associated with teat and udder structure in Canadian Angus cows thereby enhancing knowledge of the biological architecture of these traits. Thus, we performed a weighted single-step genome wide association study (WssGWAS) to identify candidate genes for teat and udder score in 1,582 Canadian Angus cows typed with the GeneSeek ® Genomic Profiler Bovine 130K SNP array. Genomically enhanced estimated breeding values (GEBVs) were converted to SNP marker effects using unequal variances for markers to calculate weights for each SNP over three iterations. At the genome wide level, we detected windows of 20 consecutive SNPs that explained more than 0.5% of the variance observed in these traits. A total of 35 and 28 windows were identified for teat and udder score, respectively, with two SNP windows in common for both traits. Using Ensembl, the SNP windows were used to search for candidate genes and quantitative trait loci (QTL). A total of 94 and 71 characterized genes were identified in the regions for teat and udder score, respectively. Of these, 7 genes were common for both traits. Gene network and enrichment analysis, using Ingenuity Pathway Analysis (IPA), signified key pathways unique to each trait. Genes of interest were associated with immune response and wound healing, adipose tissue development and morphology, and epithelial and vascular development and morphology. Genetic architecture from this GWAS confirms that teat and udder score are distinct, polygenic traits involving varying and complex biological pathways, and that genetic selection for improved teat and udder score is possible.

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Ubiquitin-specific peptidase 46 (USP46) suppresses renal cell carcinoma tumorigenesis through AKT pathway inactivation

Cited by 12 publications

References 19 publications

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

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

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

Genome-wide association study for mammary structure in Canadian Angus cows

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