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Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma.

ABSTRACT: Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor-differentiation and enhanced malignancy of lung adenocarcinoma. This study investigated the association and impact of the ubiquitin-specific peptidase 22 (USP22), an H2Bub1 deubiquitinase, on stem cell-like characteristics and cisplatin resistance in cancer-initiating cells (CIC) from primary lung adenocarcinoma. CICs were isolated, enriched, and characterized from patient-derived cancer tissues using both in vitro tumorsphere formation and in vivo xenograft assays. USP22 was determined to be predominantly expressed in CICs, a subpopulation of cells with high expression of the stem cell biomarkers, CD133 and CD44. The expression of USP22 in CICs is markedly reduced upon FBS/retinoic acid-induced differentiation. Moreover, knockdown of USP22 significantly suppressed tumorsphere formation and xenograft growth in NOD-SCID gamma (NSG) mice. Notably, USP22 and aldehyde dehydrogenase (ALDH) activity were elevated in tumorsphere cells that survived cisplatin treatment, whereas knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a predominant ALDH isozyme implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Combined, these data demonstrate that USP22, predominantly expressed in CD133+ CICs, plays a critical role in tumorigenicity and cisplatin resistance in lung adenocarcinoma.Implications: Targeting USP22 represents a potential therapeutic approach to suppress CICs in lung adenocarcinoma partially through downregulation of ALDH1A3 expression. Mol Cancer Res; 16(7); 1161-71. ©2018 AACR.

SUBMITTER: Yun X

PROVIDER: S-EPMC6030467 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma.

Yun Xinwei X Zhang Keqiang K Wang Jinhui J Pangeni Rajendra P RP Yang Lu L Bonner Melissa M Wu Jun J Wang Jami J Nardi Isaac K IK Gao Ming M Raz Dan J DJ

Molecular cancer research : MCR 20180502 7

Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor-differentiation and enhanced malignancy of lung adenocarcinoma. This study investigated the association and impact of the ubiquitin-specific peptidase 22 (USP22), an H2Bub1 deubiquitinase, on stem cell-like characteristics and cisplatin resistance in cancer-initiating cells (CIC) from primary lung adenocarcinoma. CICs were isolated, enriched, and characterized from patient-derived cancer tissues using both <i ...[more]

PMID: 29720480

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Project description:BackgroundEsophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood.Materials and methodsEighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed.ResultsWe found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/?-catenin pathway. Specifically, apatinib induced the degradation of ?-catenin and decreased its transcriptional activity through Akt/GSK-3? repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer.ConclusionOur study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/?-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.

Dataset Information

Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma.

Publications

Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma.

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