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Title:
HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway | Journal of Experimental & Clinical Cancer Research | Full Text
Description:
Background Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and KaplanāMeier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirusāmeditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumorānodeāmetastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.
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hdac, nsclc, fgf, cells, expression, cell, fig, cancer, usp, βcatenin, analysis, article, overexpression, google, scholar, metastasis, representative, patients, assay, lung, tumor, data, cas, proliferation, protein, western, significantly, results, tissues, knockdown, blotting, control, images, growth, levels, showed, progression, group, promotes, prognosis, tumors, pathway, study, correlated, upregulated, found, zhang, role, survival, performed,
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beta-catenin/t-cell factor complex hdac7-β-catenināfgf18 regulatory axis mir-29b/hdac4 epigenetic loop springer nature wnt/β-catenin signaling pathway aberrant wnt/β-catenin signaling hdac7-β-catenināfgf18 pathway mir-4465-epha2 signaling axis enzyme-linked immunosorbent assay kaplanāmeier plotter database enzyme-linked immunosorbent assays wnt/β-catenin signaling paraffin-embedded tissue microarray β-catenin related genes kaplanāmeier survival analysis β-catenin/tcf4 complex β-cateninātcf4 complex pseudo-colored luminescent images tcf-responsive promoter reporter β-catenin-fgf18 pathway crucial pro-proliferative factor relative top/fop ratio cell cycleārelated proteins additional information publisher' wild-type p53 fop luciferase activity proteināprotein interaction surfaces hdac7-enhanced nsclc progression raw rna-seq data β-catenin induced β-catenin/tcf4 interaction original hdac7-binding protein beta-catenin signalling hdac7-mediated nsclc progression hdac7-meditated nsclc progression decreased acetylation levels hdac7-mediated nsclc proliferation study-related procedures began privacy choices/manage cookies fgf18-overexpressing cells presented β-catenin pathway sharing hdac7-mediated posttranslational modification background worldwide hdac7-enhanced migratory abilities hdac7-regulated nsclc progression kaplanāmeier method received respective treatments bmc β-catenin signaling
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headline:HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway
description:Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and KaplanāMeier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirusāmeditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumorānodeāmetastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.
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headline:HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway
description:Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and KaplanāMeier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirusāmeditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumorānodeāmetastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.
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name:Kenichi Suda
affiliation:
name:Kindai University Faculty of Medicine
address:
name:Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
type:PostalAddress
type:Organization
name:Federico Cappuzzo
affiliation:
name:Istituto Nazionale Tumori IRCCS āRegina Elenaā
address:
name:Istituto Nazionale Tumori IRCCS āRegina Elenaā, Roma, Italy
type:PostalAddress
type:Organization
name:Jing Han
affiliation:
name:Tangdu Hospital, Air Force Medical University
address:
name:Department of Ophthalmology, Tangdu Hospital, Air Force Medical University, Xiāan, China
type:PostalAddress
type:Organization
email:[email protected]
name:Xiaofei Li
affiliation:
name:Air Force Medical University
address:
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
type:PostalAddress
type:Organization
email:[email protected]
name:Xiaolong Yan
url:http://orcid.org/0000-0003-2419-9707
affiliation:
name:Air Force Medical University
address:
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Department of Thoracic Surgery, Shaanxi Provincial Peopleās Hospital, The Third Affiliated Hospital of Xiāan Jiaotong University, Xiāan, China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
name:Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Xiāan Jiaotong University, Xiāan, China
name:Department of Ultrasound, Xiāan Central Hospital, Xiāan Jiaotong University, Xiāan, China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xiāan, China
name:Department of Thoracic Surgery, The Sixth Medical Center of PLA General Hospital, Beijing, China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, Italy
name:Thoracic Oncology Center, Department of Oncology-Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
name:Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
name:Istituto Nazionale Tumori IRCCS āRegina Elenaā, Roma, Italy
name:Department of Ophthalmology, Tangdu Hospital, Air Force Medical University, Xiāan, China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
name:Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, Xiāan , China
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