Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway

Lin, Hechun; Li, Jing; Cheng, Dongdong; Zhang, Xiao; Tao, Yu; Zhao, Fangyu; Geng, Qin; Zhu, Ming; Kong, Hainan; Li, Hong; Yao, Ming

doi:10.1016/j.omto.2021.02.015

Cited by 13 publications

(9 citation statements)

References 40 publications

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“…Previous studies reported a correlation between high expression of CSE1L and poor prognosis in nonsmall cell lung cancer (NSCLC) (20). Our analysis of the KM plotter Gene-Chip database con rmed that high CSE1L expression is associated with signi cantly decreased overall survival (OS) in 2166 cases of NSCLC (Fig.…”

Section: Discussionsupporting

confidence: 58%

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor

Duan

Maki

2023

Preprint

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p53 represses transcription by activating p21 expression and promoting formation of RB1-E2F1 and RBL1/RBL2-DREAM transcription repressor complexes. The DREAM complex is composed of DP1, RB-family proteins RBL1 or RBL2 (p107/p130), E2F4/5, and MuvB. We recently reported RBL2-DREAM contributes to improved therapy responses in p53 wild-type NSCLC cells and improved outcomes in NSCLC patients whose tumors express wild-type p53. In the current study we identified CSE1L as a novel inhibitor of the RBL2-DREAM pathway and target to activate RBL2-DREAM in NSCLC cells. CSE1L is an oncoprotein that promotes nuclear accumulation of histone deacetylases HDACs 1, 2, and 8 to repress gene transcription. Mocetinostat is a HDAC inhibitor in clinical trials with selectivity against HDACs 1 and 2. Knockdown of CSE1L in NSCLC cells or treatment with mocetinostat increased p21, activated RB1 and RBL2, repressed DREAM target genes, and induced toxicity in a manner that required wild-type p53. Lastly, we found high levels of CSE1L and specific DREAM-target genes are candidate markers to identify p53 wild-type NSCLCs most responsive to mocetinostat. Thus, we identified CSE1L as a critical negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC that can be indirectly targeted with HDAC1/2 inhibitors (mocetinostat) in current clinical trials. High expression of CSE1L and DREAM target genes could serve as a biomarker to identify p53 wild-type NSCLCs most responsive to this HDAC1/2 inhibitor.

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Section: Discussionsupporting

confidence: 58%

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor

Duan

Maki

2023

Preprint

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“…A previous study showed that ACOT11 can promote the proliferation, migration, and invasion of lung cancer cells by binding with CSE1L ( 47 ). CSE1L can regulate the MAPK pathway and promote the development of lung cancer by interacting with p65 ( 15 ). Another study reported that CSE1L silencing impaired the cell proliferation, invasion, and migration of lung cancer cells, and that the expression of STAT3 and MET protein was decreased; the apoptosis-related marker protein c-PAR P was induced, which indicated that cell proliferation and antiapoptosis may be regulated by CSE1L via the MET–STAT3 pathway ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the study also found that after tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ( NNK ) exposure or transfection with CRM1 vector, the overexpression of CRM1 in the lung epithelial cell line BEAS-2B led to cellular transformation, which suggests that the up-regulation of CRM1 may be an important pathway for malignant transformation of lung epithelial cells ( 14 ). CSE1L interacts with p65 and activates nuclear factor-κB ( NF-κB ), and Mitogen-activated protein kinase ( MAPK ) signaling pathway promotes NSCLC proliferation and inhibits apoptosis ( 15 ). However, the expression level, genetic variation, immune infiltration and biological function of different exportins in LUAD and LUSC was well as their relationship with prognosis of patients with LUAD and LUSC have not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive bioinformatics analysis on exportins in lung adenocarcinoma and lung squamous cell carcinoma

Pan¹,

Huang²,

Li³

et al. 2023

J Thorac Dis

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Background: Lung cancer is one of the most common malignant tumors in the world. Exportins are closely associated with the cellular activity and disease progression in a variety of different tumors. However, the expression level, genetic variation, immune infiltration, and biological function of different exportins in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), as well as their relationship with the prognosis of patients with LUAD and LUSC have not been fully clarified. Methods: To analyze the differential expression, prognostic value, genetic variation, biological function, and immune cell infiltration of exportins in patients with LUAD and LUSC, the ONCOMINE; UALCAN; Human Protein Atlas (HPA); Kaplan-Meier plotter; cBioPortal; Search Tool for the Retrieval of Interacting Genes/Proteins (STRING); Database for Annotation, Visualization, and Integrated Discovery (DAVID);Tumor Immune Estimation Resource (TIMER); and LinkedOmics databases were used in this study. Results:The transcriptional and protein expression levels of CSE1L and XPO1/5/6/7 were increased in patients with LUAD and LUSC, and the increased transcriptional levels of CSE1L and XPO5/6/7 were related to worse prognosis. An increased transcriptional level of XPO1 was associated with a better prognosis.These results indicated that CSE1L and XPO1/5/6/7 may be potential prognostic biomarkers for the survival of patients with LUAD and LUSC. Moreover, the high mutation rate of exportins in non-small cell lung cancer was 50.48%, and the largest proportion of mutations included high messenger RNA expression.The expression of exportins was significantly correlated with the infiltration of various immune cells.Differentially expressed exportins could regulate the occurrence and development of LUAD and LUSC by involving a variety of microRNAs and transcription factor E2F1.Conclusions: Our study provides novel insights into the selection of prognostic biomarkers of exportins in LUAD and LUSC.

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“…A previous study shown that ACOT11 can promote the proliferation, migration and invasion of lung cancer cells by binding with CSE1L 48 . CSE1L can regulate the MAPK pathway and promote the development of lung cancer by interacting with p65 49 . Other studies have con rmed that CSE1L silencing impaired the cell proliferation, invasion and migration of lung cancer cells, and the expression of STAT3 and MET protein expression was decreased, then, the apoptosis related marker protein c-PARP was induced, which indicated that the regulation of CSE1L on cell proliferation and anti-apoptosis may be through MET-STAT3 pathway 50 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive bioinformatics analysis on exportins in lung adenocarcinoma and lung squamous cell carcinoma

Pan

Huang

2022

Preprint

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Background Lung cancer is one of the most common malignant tumors in the world. Exportins are closely associated with the cellular activity and disease progression in a variety of different tumors. However, the expression level, genetic variation, immune infiltration and biological function of different exportins in LUAD and LUSC and their relationship with the prognosis of LUAD and LUSC patients have not been fully clarified. Methods In this study, ONCOMINE, UALCAN, HPA, Kaplan-Meier plotter, cBioPortal, STRING, DAVID, TIMER and LinkedOmics databases were used to analyze the differential expression, prognostic value, genetic variation, biological function and immune cell infiltration of exportins in patients with LUAD and LUSC. Results The transcriptional and protein expression levels of CSE1L and XPO1 / 5 / 6 / 7 were increased in LUAD and LUSC patients, and the increased transcriptional levels of CSE1L and XPO5 / 6 / 7 were related to worse prognosis. The increased transcriptional level of XPO1 suggested a better prognosis. These results indicated that CSE1L and XPO1 / 5 / 6 / 7 may be potential prognostic biomarkers for the survival of patients with LUAD and LUSC. Besides, the high mutation rate of exportins in NSCLC was 50.48%, and the largest proportion of mutations was high mRNA expression. The expression of exportins was significantly correlated with the infiltration of various immune cells. Differentially expressed exportins could regulate the occurrence and development of LUAD and LUSC by involving a variety of miRNAs and transcription factor E2F1. Conclusions Our study could provide novel insights for the selection of prognostic biomarkers of exportins in LUAD and LUSC.

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Nuclear export protein CSE1L interacts with P65 and promotes NSCLC growth via NF-κB/MAPK pathway

Cited by 13 publications

References 40 publications

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor

CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2 inhibitor

Comprehensive bioinformatics analysis on exportins in lung adenocarcinoma and lung squamous cell carcinoma

Comprehensive bioinformatics analysis on exportins in lung adenocarcinoma and lung squamous cell carcinoma

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