Gliomas represent more than a quarter of all CNS tumors. Limited treatment options together with high mortality and disability rates constitute a significant burden on healthcare and the economy, underscoring the need to identify transformative therapeutic targets to combat this malignancy.

Cancer germline antigens, also known as cancer-testis antigens (CTAs), are involved in various oncogenic signaling pathways that promote tumor growth and inhibit apoptosis. CTAs are expressed variably in gliomas, serving as prognostic markers and highly promising therapeutic targets. Among these, the ATPase family AAA domain-containing protein 2 (ATAD2) has been implicated in the tumorigenesis of multiple cancers; however, its regulatory role in gliomas remains poorly understood.

In a recent study published in the Genes & Diseases journal, researchers at the First Affiliated Hospital of Hainan Medical University and Tongji University School of Medicine provide mechanistic insights into how ATAD2 influences glioma progression.
By analyzing the gene expression profiles in the CGGA cohort, the authors showed that gliomas can be classified into two distinct subtypes based on the clustering of CTA-related genes. The authors developed CTARS, a risk score correlating the expression of 10 CTA genes and prognosis, which was subsequently validated as an independent prognostic indicator. Together with other independent variables, such as age, tumor grade, and 1p/19q status, the CTARS was used to construct a personalized prognostic nomogram that effectively predicts clinical outcomes in glioma patients.


Bioinformatics revealed that the ATAD2 enzyme has bioactive compounds and a druggable structure, while high mRNA and protein expression was observed in the glioma cohort from multiple databases, suggesting that ATAD2 expression is closely associated with clinical and pathological characteristics.


Further experiments with glioma cell lines—LN229, U251MG, and T98G—showed that ATAD2 is predominantly localized within the nucleus. ATAD2 knockdown suppressed tumor cell proliferation, growth, and migration, while ATAD2 overexpression exerted opposite effects, both in vitro and in vivo, highlighting its role in promoting glioma progression.
Mechanistically, ATAD2 exhibits a reciprocal regulatory relationship with E2F1 and acts synergistically to enhance PDK1 transcriptional activity in glioma cells. Based on the co-expression of these genes, it was observed that glioma patients with high expression of all three genes have poorer prognoses, underlining the ATAD2-E2F1-PDK1 axis as a potential clinical prognostic biomarker.


The authors acknowledge certain limitations, which include (i) the need for a larger clinical cohort, (ii) more in vivo experiments involving subcutaneous and intracranial orthotopic tumors following ATAD2 overexpression, (iii) the need for more investigations into the regulatory role of ATAD2, (iv) the efficacy of combining ATAD2 inhibitors with dichloroacetate, and (v) its role in chemotherapy resistance.
In conclusion, this study highlights CTARS as a valuable independent prognostic marker and shows that ATAD2 promotes glioma progression by synergizing with E2F1 to co-activate PDK1.

Reference
Title of the original paper: Druggable target ATAD2 enhances the malignant progression and cooperates with E2F1 to up-regulate PDK1 expression in glioma

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101810

Funding Information:

1. National Nature Science Foundation of China (No. 82060456)
2. Finance science and technology project of Hainan province (China) (No. ZDYF2022SHFZ088)
3. Hainan Province “South China Sea Rising Star” Science and Technology Innovation Talent Platform Project (China) (No. NHXXRCXM202351)
4. The project of Hainan Provincial Postdoctoral Science Foundation (China) (No. 395995)
5. Hainan Provincial Natural Science Foundation of China (No. 821MS137)
6. Key Research and Development Special Fund of the Hainan Provincial Department of Science and Technology (China) (ICAC, Grant No. SQ2025SLYZL0001)

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