<p>Knockdown of ATAD2 Inhibits Proliferation and Tumorigenicity Through the Rb-E2F1 Pathway and Serves as a Novel Prognostic Indicator in Gastric Cancer</p>

Abstract

The aim of the present study was to examine the expression of ATAD2 in gastric cancer (GC) specimens and to evaluate its correlation with clinicopathologic features, including survival of GC patients. The potential roles of ATAD2 in the GC cell proliferation, apoptosis, and tumour growth were further explored. Materials and Methods: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) were applied to determine the mRNA and protein expression of ATAD2 in GC and corresponding adjacent nontumourous specimens. The relationship between ATAD2 expression and clinicopathological features of GC patients was analysed. Kaplan-Meier analysis was performed to assess the prognostic value of ATAD2 expression levels. The proliferation, colony formation, apoptosis and tumorigenesis roles of ATAD2 were measured using in vitro and in vivo experiments. Results: The expression of ATAD2 mRNA and protein was overexpressed in GC tissues compared with corresponding adjacent non-tumourous tissues. ATAD2 expression was significantly correlated with tumour size, tumour differentiation, and clinical tumour-nodemetastasis (TNM) stage. Patients with high ATAD2 expression were likely to experience significantly shorter postoperative overall survival (OS) and disease-free survival (DFS). Multivariate Cox analysis suggested ATAD2 as an independent variable for OS and DFS. Knockdown of ATAD2 significantly suppressed cell proliferation, colony formation in vitro and tumorigenicity in vivo. Cell cycle and apoptotic assays showed that the anti-proliferative effect of pLV-ATAD2 shRNA was mediated by arresting cells in the G1 phase and inducing cell apoptosis. Silencing of ATAD2 reduced the expression of cyclinD1, ppRb, E2F1 and cyclinE and upregulated the expression of cleaved-PARP and cleaved-Caspase 3. Conclusion: Our study indicated that ATAD2 plays an important role in the process of tumorigenesis and progression in GC, and it could serve as a novel prognostic biomarker and a therapeutic target for the treatment of GC patients.

The association between bromodomain proteins and cancer stemness in different solid tumor types

“…The pRB‐E2F pathway tightly regulates ATAD2 expression, which is essential for the growth of normal and cancer cells. As a direct binding partner for both E2F and c‐Myc, ATAD2 induces the expression of genes that facilitate cell cycle progression and inhibition of apoptosis in many different types of cancers, including breast, lung and prostate tumors 48 . Also, Wu et al 49 proposed that ATAD2 might cooperate with the c‐Myc to control the level of SMO and GLI1 , leading to the Hedgehog (Hh) pathway and feedback of the Hh pathway activation in liver tumor cells.…”

Tumor-Promoting ATAD2 and Its Preclinical Challenges

“…The pRb is a CDK4/CDK6 target, and as soon as cyclin D1 combines with CDK4/CDK6, pRb is phosphorylated and ppRb is liberated from E2F. ATAD2 binds to the transcription factors E2F and c-MYC to promote proliferation-related and anti-apoptotic gene expression, causing the occurrence and development of GC [ 21 , 22 ]. Furthermore, ATAD2 may interact with estrogen receptor 1 (ESR1) to regulate nuclear receptor coactivator 1 (NCOA1) and protein arginine methyltransferase 1 (PRMT1) to cause epigenetic changes in GC ( Figure 2 ) [ 23 ].…”

“…It has been found that ATAD2 can be used as one of the candidate genes for paclitaxel resistance and become a potential new marker for predicting paclitaxel resistance in patients with peritoneal metastasis of GC [ 106 ]. ATAD2 overexpression is correlated with the clinical stage, depth of tumor invasion, lymph node, and distant metastasis of GC and is an independent factor in the prognosis of GC patients [ 21 , 107 ].…”

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

“…Moreover, SPIN1 could form a positive feedback loop with E2F1 to promote the development of GC ( 128 ). Furthermore, ATAD2 knockdown in GC cells led to reduced levels of cyclin D1, cyclin E, E2F1 and RB phosphorylation, thus inhibiting proliferation and cell cycle progression ( 129 ). Interestingly, decrease of intracellular chloride ion concentration could increase the level of p21 and reduce the phosphorylation of CDK2 and RB ( 130 ).…”