ATAD2 drives colorectal cancer progression by regulating TRIM25 expression via a positive feedback loop with E2F transcriptional factors.

ATPase family AAA domain-containing protein 2 (ATAD2) is highly expressed in a variety of cancer types, and acts as a co-activator of androgen and estrogen receptors, as well as MYC and E2F transcription factors, to promote tumor cell proliferation. However, the regulation of ATAD2 and its related mechanisms are still elusive. Here, we show that ATAD2 protein was stabilized during DNA damage response in colorectal cancer (CRC) cells. TRIM25, an oncogenic ubiquitin E3 ligase, can interact with ATAD2 and stabilize ATAD2 upon genotoxic insult. We further demonstrated that ATAD2 played a tumor promoting role in CRC and acted as a transcriptional co-activator of E2Fs to promote the expression of TRIM25. Thus, our results revealed an unknown ATAD2-E2Fs-TRIM25 positive feedback loop that drove CRC progression.