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

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.

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration

“…In terms of mechanism, HDAC7 could interact with β -catenin and enhance its nucleus translocation via decreasing β -catenin acetylation level at Lys49 and phosphorylation level at Ser45 to promote fibroblast growth factor 18 expression which induced the malignant biological behaviors of NSCLC, and the HDAC7 expression could be further stabilized by USP10. The similar mechanism could also be found in the study of HDAC6 [ 30 , 31 ]. Besides, several articles have indicated the roles of USP10 in pancreatic cancer.…”

WNT5A promotes the metastasis of esophageal squamous cell carcinoma by activating the HDAC7/SNAIL signaling pathway

“…In our study, HDAC7 knockdown reversed WNT5A overexpression induced changes in the levels of EMT markers by decreasing SNAIL levels. Furthermore, our research group recently found that HDAC7 increased SNAIL protein levels by regulating fibroblast growth factor 18 (FGF18) in non-small cell lung cancer [ 52 ]. As mentioned above, we speculate that SNAIL regulates E-cadherin expression by recruiting HDAC7 to form a corepressor complex, HDAC7 deacetylates lysine residue sites on the SNAIL protein to affect its stability and regulate the expression of E-cadherin, or HDAC7 indirectly promotes SNAIL by regulating other factors, but these hypotheses require further exploration.…”

Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: Assessing its role in tumor prognosis and immune response

“…Thus, USP10 might affect cisplatin resistance by deubiquitinating and thereby stabilizing the oncogenic protein histone deacetylase 6 (HDAC6) ( 36 , 37 ). Another study showed that USP10 plays an important regulatory role in NSCLC via deubiquitinating and stabilizing histone deacetylase 7 (HDAC7), and that USP10 inhibition could significantly accelerate HDAC7 degradation and impair NSCLC proliferation and migration ( 38 ).…”