ATAD2, an ATPase family AAA domain-containing protein 2, is a highly conserved bromodomain family protein. It functions mainly through its AAA ATPase and bromodomain, acting as an epigenetic decoder, transcription factor or co-activator. ATAD2 is involved in crucial cellular activities such as transcriptional regulation, DNA replication, and protein modification. It participates in multiple oncogenic signaling pathways, including Rb/E2F-cMyc, steroid hormone signaling, p53 and p38-MAPK-mediated apoptotic, AKT, hedgehog, HIF1α, and EMT pathways [1].

In human cancer cell lines and mouse embryonic stem cells, knockout (KO) of ATAD2 leads to an accumulation of the histone chaperone HIRA. ChIP-seq mapping in Atad2 KO mouse ES cells shows that HIRA and FACT are trapped on nucleosomes at the transcription start sites of active genes, resulting in abnormal nucleosome presence on TSS-associated nucleosome-free regions, highlighting its role in chromatin dynamics regulation [2]. In ovarian cancer, ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. Disrupting the MYBL2-ATAD2 signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model [3]. In pancreatic cancer cells, ATAD2 silencing sensitizes cells to gemcitabine and radiation, enhancing the efficacy of their combination treatment [4].

In conclusion, ATAD2 is essential for normal chromatin dynamics and cellular activities. Through KO/CKO mouse models and cell-based functional studies, its role in promoting tumorigenesis, cancer progression, chemoresistance in various malignancies like ovarian, pancreatic, and colorectal cancers has been revealed. These findings suggest that targeting ATAD2 could be a potential strategy for cancer therapy.