HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway

Journal of Experimental & Clinical Cancer Research

Zhiqiang Ma¹  Fei Gao²  Fabrizio Tabbò³  Jing Han⁴  Yujiao Zhang⁵  Kai Guo⁶  Xiaolong Yan⁷  Jiao Zhang⁷  Yingtong Feng⁷  Xiaofei Li⁷  Changjian Shao⁷  Zhipei Zhang⁷  Shouyin Di⁸  Lu Han⁹  Kenichi Suda^1,10  Federico Cappuzzo^1,11  Simon Ekman^1,12 

[1] Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital;Department of Neurosurgery, Tangdu Hospital, Air Force Medical University;Department of Oncology, University of Turin, San Luigi Hospital;Department of Ophthalmology, Tangdu Hospital, Air Force Medical University;Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Xi’an Jiaotong University;Department of Thoracic Surgery, Shaanxi Provincial People’s Hospital, The Third Affiliated Hospital of Xi’an Jiaotong University;Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University;Department of Thoracic Surgery, The Sixth Medical Center of PLA General Hospital;Department of Ultrasound, Xi’an Central Hospital, Xi’an Jiaotong University;Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine;Istituto Nazionale Tumori IRCCS “Regina Elena”;Thoracic Oncology Center, Department of Oncology-Pathology, Karolinska University Hospital, Karolinska Institutet;

关键词: NSCLC;    HDAC7;    FGF18;    β-catenin;    USP10;   

DOI  :  10.1186/s13046-022-02266-9

来源: DOAJ

【 摘 要 】

Abstract 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 Kaplan–Meier 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 lentivirus–meditated 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, tumor–node–metastasis (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.

【 授权许可】

Unknown