Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

Lin, Jing; Sun, Tong; Ji, Lin; Deng, Wuguo; Roth, Jack A.; Minna, John D.; Arlinghaus, Ralph B.

doi:10.1038/sj.onc.1210500

Cited by 55 publications

(70 citation statements)

References 21 publications

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“…Our recent findings demonstrate that activated c-Abl tyrosine kinase may also play a role in non-small cell lung cancer (NSCLC) (Lin et al, 2005(Lin et al, , 2007. Activation of c-Abl tyrosine kinase in some solid tumors is further supported by studies from Plattner and co-workers (Srinivasan and Plattner, 2006;Srinivasan et al, 2008), whose findings indicate active c-Abl tyrosine kinase plays a role in aggressive human breast cancer cell lines.…”

Section: Introductionsupporting

confidence: 48%

“…We therefore tested the effects of imatinib on colony formation of H1299 cells in soft agar. Imatinib treatment (concentrations 1-5 mM) strongly inhibited the colony-forming ability of H1299 cells; both the number and size of colonies were inhibited (Lin et al, 2007). We note that imatinib at these low concentrations had little effect on the proliferation of the H1299 cells in cell culture.…”

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 84%

“…At the time Fus1 was not known to be involved with c-Abl, nor was it known that Fus1 may be an inhibitor of the c-Abl tyrosine kinase. We verified Fus1's ability to downregulate Abl kinase by showing that the abovementioned Fus1 peptide strongly inhibited a purified full-length human-activated c-Abl tyrosine kinase (Lin et al, 2007).…”

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 91%

“…Clues as to its possible activities can be gained from structure-function relationships of wild type and mutant forms of the Fus1 protein (Figure 1). A deletion mutant of FUS1 (FUS 1-80) lacks its tumor suppressor function (Lin et al, 2007). Thus, the C-terminal 30 amino acids within the Fus1 protein is important for its tumor suppressor function and for its ability to downregulate c-Abl.…”

Section: Possible Mechanism Of the Inhibition Of C-abl Tyrosine Kinasmentioning

confidence: 99%

“…This Fus1 peptide was not functional unless a stearate group was linked to the N terminus. (Lin et al, 2007). At the time Fus1 was not known to be involved with c-Abl, nor was it known that Fus1 may be an inhibitor of the c-Abl tyrosine kinase.…”

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 99%

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Activated c-Abl tyrosine kinase in malignant solid tumors

Lin

Arlinghaus

2008

Oncogene

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Section: Introductionsupporting

confidence: 48%

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 84%

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 91%

Section: Possible Mechanism Of the Inhibition Of C-abl Tyrosine Kinasmentioning

confidence: 99%

Section: Activated C-abl In Non-small Cell Lung Cancermentioning

confidence: 99%

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Activated c-Abl tyrosine kinase in malignant solid tumors

Lin

Arlinghaus

2008

Oncogene

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USP7 promotes non‐small‐cell lung cancer cell glycolysis and survival by stabilizing and activating c‐Abl

He,

Jiang,

Zhong

et al. 2023

Clinical & Translational Med

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BackgroundAbelson tyrosine kinase (c‐Abl) is frequently mutated and highly expressed, and promotes non‐small‐cell lung cancer (NSCLC) survival, metastasis and tumorigenesis. c‐Abl could also be modified through ubiquitination, but the underlying mechanism is not well understood.MethodsMass spectrometry assays were performed to search c‐Abl deubiquitination enzymes. The molecular mechanism was determined using Co‐IP assays, pull‐down assays, Western blotting upon gene knockdown or overexpression. Cell lines and animal models were used to investigate the role of c‐Abl and USP7 in NSCLC. EdU staining assay and Transwell assay were performed to evaluate the proliferation and migration ability of NSCLC cells, respectively.ResultsUbiquitin‐specific protease 7 (USP7) is found to upregulate c‐Abl via the deubiquitinase screen. USP7 interacts with c‐Abl and decreases its K48‐linked polyubiquitination, thereby increasing the stability of c‐Abl. In addition to the wild‐type one, c‐Abl mutants can also be deubiquitinated and stabilized by USP7. Moreover, USP7 promotes c‐Abl accumulation in cytoplasm by increasing its binding to 14‐3‐3α/β and activates the oncogenic c‐Abl signalling pathway. Furthermore, the USP7/c‐Abl axis promotes NSCLC cell glycolysis by direct phosphorylating and stabilizing hexokinase‐2 (HK2). Knockdown of USP7 or c‐Abl suppresses NSCLC cell glycolysis and reduces lactate production. Further studies revealed that overexpression of USP7 facilitates NSCLC cell growth and metastasis as well as xenograft growth in nude mice, while these activities are suppressed with USP7 or c‐Abl being knocked down.ConclusionsUSP7 is a deubiquitinase of c‐Abl and upregulates its oncogenic activity. USP7 promotes NSCLC cell metabolism by activating c‐Abl and HK2. Targeting the USP7/c‐Abl/HK2 axis might be a potential strategy to the precision therapy of NSCLC.

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Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

Qiu

Gazdar

et al. 2017

Genes Chromosomes & Cancer

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The accurate classification of non-small cell lung carcinoma (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is essential for both clinical practice and lung cancer research. Although the standard WHO diagnosis of NSCLC on biopsy material is rapid and economic, more than 13% of NSCLC tumors in the USA are not further classified. The purpose of this study was to analyze the genome-wide pattern differences in copy number variations (CNVs) and to develop a CNV signature as an adjunct test for the routine histopathologic classification of NSCLCs. We investigated the genome-wide CNV differences between these two tumor types using three independent patient datasets. Approximately half of the genes examined exhibited significant differences between LUAD and LUSC tumors and the corresponding non-malignant tissues. A new classifier was developed to identify signature genes out of 20 000 genes. Thirty-three genes were identified as a CNV signature of NSCLC. Using only their CNV values, the classification model separated the LUADs from the LUSCs with an accuracy of 0.88 and 0.84, respectively, in the training and validation datasets. The same signature also classified NSCLC tumors from their corresponding non-malignant samples with an accuracy of 0.96 and 0.98, respectively. We also compared the CNV patterns of NSCLC tumors with those of histologically similar tumors arising at other sites, such as the breast, head, and neck, and four additional tumors. Of greater importance, the significant differences between these tumors may offer the possibility of identifying the origin of tumors whose origin is unknown.

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Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

Cited by 55 publications

References 21 publications

Activated c-Abl tyrosine kinase in malignant solid tumors

Activated c-Abl tyrosine kinase in malignant solid tumors

USP7 promotes non‐small‐cell lung cancer cell glycolysis and survival by stabilizing and activating c‐Abl

Genome‐wide copy number variation pattern analysis and a classification signature for non‐small cell lung cancer

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