ATAD2 predicts poor outcomes in patients with ovarian cancer and is a marker of proliferation

Abstract

The oncogene ATPase family AAA domain-containing protein 2 (ATAD2) has been demonstrated to promote malignancy in a number of different types of tumor; however, its expression and role in ovarian cancer (OC) remain unknown. In the present study, it was demonstrated that ATAD2 acts as both a marker and a driver of cell proliferation in OC. Immunohistochemistry (IHC) and bioinformatics analyses were used to evaluate ATAD2 expression in OC, and multi-omics integrated analyses were used to dissect which factor resulted in its upregulation. Multiplex IHC assay was used to reveal the specific expression of ATAD2 in proliferating OC cells. CRISPR-Cas9-mediated gene editing was performed to investigate the effect of ATAD2 deletion on OC proliferation. The results demonstrated that ATAD2 is elevated in primary OC tissues compared with the adjacent normal tissue and metastases from the stomach. Genetic copy number amplification is a primary cause resulting in upregulation of ATAD2, and this was most frequently observed in OC. High ATAD2 expression was associated with advanced progression and predicted an unfavorable prognosis. ATAD2 could be used to identify cases of OC with a high proliferation signature and could label proliferating cells in OC. CRISPR-Cas9-mediated ATAD2 deletion resulted in a significant decrease in both cell proliferation and colony formation ability. Mechanistically, ATAD2-knockdown resulted in deactivation of the mitogen-activated protein kinase (MAPK) pathways, particularly the JNK-MAPK pathway, resulting in suppression of proliferation. Collectively, the data from the present study demonstrated that the ATD2 gene was frequently amplified and protein expression levels were upregulated in OC. Therefore, ATAD2 may serve as an attractive diagnostic and prognostic OC marker, which may be used to identify patients with primary OC, whom are most likely to benefit from ATAD2 gene-targeted proliferation intervention therapies.

Histone H2B ubiquitination mediated chromatin relaxation is essential for the induction of somatic cell reprogramming

“…Among the 594 genes, 49 genes were also associated with decreased SOX2 signals upon Rnf20 knockout (Figure 4J ). Further analysis revealed that the genes with decreased SOX2 binding and downregulated expression in Rnf20 knockout reprogrammable cells are involved in kinetochore organization, DNA conformation change and DNA replication 42 , 43 (Figure 4K‐4O ). These results suggest a positive correlation between SOX2 binding and gene expression, and that the knockout of Rnf20 might affect the recruitment of reprogramming TFs to their target genes, ultimately impeding the initiation of ‘first‐wave’ gene expression.…”

“…Among the 594 genes, 49 genes were also associated with decreased SOX2 signals upon Rnf20 knockout (Figure 4J). Further analysis revealed that the genes with decreased SOX2 binding and downregulated expression in Rnf20 knockout reprogrammable cells are involved in kinetochore organization, DNA conformation change and DNA replication 42,43 (Figure 4K-4O).…”

Tumor-Promoting ATAD2 and Its Preclinical Challenges

“…ATAD2 is both a marker and driver of cell proliferation in OC. ATAD2 may drive OC cell proliferation through the MAPK pathway and is also involved in the process of miR-372 inhibiting OC cell proliferation [ 37 , 38 ]. ATAD2 participates in the highly activated PI3K/AKT oncogenic channel, while miR-200b-5p targets the inhibition of ATAD2 expression and regulates the PI3K/AKT pathway to suppress proliferation and accelerate apoptosis in OC cells [ 39 ].…”

Adeno-associated virus vector-mediated gene therapy for the treatment of ovarian cancer: a literature review

“…A study by Xie et al demonstrated that delivering AAVrh.10 (a rhesus serotype 10 adeno-associated viral vector) packed with bevacizumab to a peritoneal model of ovarian cancer resulted in a 90% reduction in tumor development and an 82% reduction in angiogenesis, as well as longer survival ( 18 ). Combining current therapeutic approaches with gene editing to precisely target genes, inhibit specific oncogenes to reduce tumor cell proliferation ( 19 , 20 ) or examine the sensitivity of ovarian cancer cells to medications with the help of gene editing, and combine immunotherapy ( 21 ) to improve survival rates are increasingly being used in ovarian cancer. A secure and efficient delivery mechanism is necessary to guarantee the efficacy of gene therapy.…”