Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma

Cox, Jesse L.; Wilder, Phillip J.; Wuebben, Erin L.; Ouellette, Michel; Hollingsworth, Michael A.; Rizzino, Angie

doi:10.4161/cbt.29182

Cited by 27 publications

(30 citation statements)

References 46 publications

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“…USP9X knockdown reduced anchorage-dependent growth and WP1130 induced significant cytotoxicity in 5 PDAC cell lines, which were felt to represent the malignancy at a more advanced stage. 22 In a related vein, USP9X downregulation by pemetrexed appears to reduce MCL1 and increase apoptosis of NSCLC cells treated with this cytotoxic agent.…”

Section: Discussionmentioning

confidence: 99%

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

Kushwaha

O’Leary

Cron

et al. 2015

Cancer Biology & Therapy

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Background and Purpose: Radiotherapy (RT) is vital for the treatment of locally advanced non-small cell lung cancer (NSCLC), yet its delivery is limited by tolerances of adjacent organs. We sought therefore to identify and characterize gene targets whose inhibition may improve RT. Materials and Methods: Whole genome pooled shRNA cytotoxicity screens were performed in A549 and NCI-H460 using a retroviral library of 74,705 sequences. Cells were propagated with or without daily radiation Monday-Friday. Radiosensitization by top differential dropout hits was assessed by clonogenic assays. Apoptosis was assessed using a caspase 3/7 cell-based activity assay and by annexin V-FITC and PI staining. MCL1 expression was assessed by qPCR and Western blotting. Results: USP9X, a deubiquitinase, was a top hit among druggable gene products. WP1130, a small molecule USP9X inhibitor, showed synergistic cytotoxicity with IR. MCL1, an anti-apoptotic protein deubiquitinated by USP9X, decreased with USP9X inhibition and IR. This was accompanied by increases in caspase 3/7 activity and apoptosis. In a panel of NSCLC lines, MCL1 and USP9X protein and gene expression levels were highly correlated. Lines showing high levels of MCL1 expression were the most sensitive to USP9X inhibition. Conclusions: These data support the use of MCL1 expression as a predictive biomarker for USP9X inhibitors in NSCLC therapy.

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Section: Discussionmentioning

confidence: 99%

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

Kushwaha

O’Leary

Cron

et al. 2015

Cancer Biology & Therapy

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“…T3M4, BxPC3, and HPAF-II PDAC cells have been described previously [63]. L3.6 PDAC cells were obtained from D. Billadeau (Mayo Clinic, Rochester Minn).…”

Section: Methodsmentioning

confidence: 99%

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.

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“…Several previous reports presented that USP9X was a cancer promoter in other malignant solid tumors, including lung cancer (5), breast cancer (6,7), esophageal carcinoma (8), colorectal carcinoma (9,10), prostate cancer (11) and pancreatic cancer (14). Cox et al (16) downregulated the USP9X expression using short hairpin RNA, which resulted in a reduction in the growth of human PDAC cells, indicating that USP9X serves as an oncogene. Notably, it was also reported that the growth of PDAC cell lines was impaired by deubiquitinating protease inhibitor WP1130, which revealed that USP9X may promote PDAC cell growth (16).…”

Section: Discussionmentioning

confidence: 99%

“…Cox et al (16) downregulated the USP9X expression using short hairpin RNA, which resulted in a reduction in the growth of human PDAC cells, indicating that USP9X serves as an oncogene. Notably, it was also reported that the growth of PDAC cell lines was impaired by deubiquitinating protease inhibitor WP1130, which revealed that USP9X may promote PDAC cell growth (16). We hypothesized that USP9X contributes to PDAC by a relatively complicated mechanism involving other participants, including an association with a Kras gene mutation (15), which requires further studies to verify, although Cox et al (16) argued that there is a context-dependent function of USP9X in different stages of PDAC.…”

Section: Discussionmentioning

confidence: 99%

“…However, a report noted that the knockout of USP9X enhances the transformation and protects cancer cells from anoikis in a murine model of PDAC, indicating that USP9X behaves as a tumor suppressor (15). The data of another research argued that USP9X promoted cell growth for established PDAC tumor cells and served a context-dependent role in PDAC (16).…”

Section: Introductionmentioning

confidence: 99%

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Decreased expression of USP9X is associated with poor prognosis in Chinese pancreatic ductal adenocarcinoma patients

et al. 2018

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Abstract. The present study aimed to investigate the expression level of ubiquitin specific peptidase 9X (USP9X) and its clinical significance in Chinese patients with pancreatic ductal adenocarcinoma (PDAC). The mRNA expression levels of USP9X in 30 paired PDAC tissue samples were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of USP9X was analyzed by immunohistochemistry (IHC) in a tissue microarray containing 205 PDAC specimens. All analyses were performed by SPSS 20.0 and GraphPad Prism 5.0 software. The USP9X mRNA level was significantly decreased in 18/30 (60.0%) PDAC tissue samples compared with matched surrounding non-tumor tissue samples. The results of IHC revealed that decreased expression of USP9X was inversely associated with liver metastasis (P= 0.032). Kaplan-Meier survival curves indicated that patients with high expression of USP9X presented a longer clinical overall survival time (P<0.001). Univariate and multivariate COX regression analysis revealed that USP9X protein expression level was a significant, and independent prognostic factor for the overall survival rate of patients with PDAC. The results of the present study indicate that USP9X may serve as a candidate tumor suppressor and prognostic biomarker in PDAC.

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Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma

Cited by 27 publications

References 46 publications

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

Decreased expression of USP9X is associated with poor prognosis in Chinese pancreatic ductal adenocarcinoma patients

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