ATAD2 interacts with C/EBPβ to promote esophageal squamous cell carcinoma metastasis via TGF-β1/Smad3 signaling

Abstract

Background Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated. Methods The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay. Results We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPβ. ATAD2 directly interacted with C/EBPβ and promoted its nuclear translocation, which directly bound to the promoter region of TGF-β1 and activated its expression. Further, we demonstrated that TGF-β1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-β signaling induced Snail expression and the subsequent epithelial-mesenchymal transition. Conclusion Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPβ/TGF-β1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.

Characterization of the Immune Infiltration Landscape and Identification of Prognostic Biomarkers for Esophageal Cancer

“…Surgical removal is the conventional treatment for most types of ESCA. However, many patients still show local recurrence or distant metastasis within a short time after surgery [2,3]. Although surgery, radiotherapy, and chemotherapy have improved the survival rate of ESCA patients, the prognosis of ESCA remains poor, and the current 5-year overall survival (OS) rate is only 15%-25% [4].…”

Adiponectin ameliorates hypertrophic scar by inhibiting Yes-associated protein transcription through SIRT1-mediated deacetylation of C/EBPβ and histone H3

“…Among them, the regulatory potential score and data support of C/EBPβ are prominent ( Figure 7 A). As an important transcription factor, C/EBPβ has been reported to participate in physiological activities such as neural signal transduction, cell proliferation, and epidermal-mesenchymal transition by regulating the expression of APOE, TGFβ1, and α-SMA ( Xia et al., 2021 ; Cao et al., 2021 ; Ding et al., 2021 ). This is related to the pathogenesis of Alzheimer’s disease, cancer, fibrosis, and other diseases.…”

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target

“…Studies have shown that the loss of ATAD2 results in decreased protein expression of EMT to impede cancer cell migration and invasion 43 . Silencing ATAD2 inhibited ESCC cell growth and lung metastasis in vivo , and the knockdown of ATAD2 inhibited ESCC migration and invasion in vitro 41 . Additionally, the reduction in ATAD2 could induce a decrease in N-cadherin and Vimentin and an increase in E-cadherin, which is also beneficial for metastasis inhibition 44 (Figure 3 E) .…”

“…While in lung adenocarcinoma, the knockdown of ATAD2 affects glucose metabolism in cancer cells by regulating [18F] FDG uptake and lactate production through the AKT-GLUT1 / HK2 pathway 39 . In addition, silencing ATAD2 also inhibits the growth and colony formation ability of esophageal squamous cell carcinoma (ESCC) cells, and significantly inhibits ESCC tumor growth in vitro 41 .…”