ATAD2 and TWIST1 Interaction Promotes MYC Activation in Colorectal Carcinoma.

Abstract

ATPase family AAA domain-containing protein 2 (ATAD2) is significantly up-regulated in many cancer types and contributes to poor patient outcomes. ATAD2 exhibits a multidomain architecture comprising an N-terminal acidic domain, two AAA+ ATPase domains, a bromodomain, and a C-terminal domain. The AAA+ ATPase domain facilitates protein oligomerization and ATP binding, while the bromodomain recognizes acetylated lysine in histones and nonhistone proteins. ATAD2 involvement in cancer extends across multiple signaling pathways, such as Rb-E2F1, PI3K/AKT, and TGF-β1/Smad3, which promotes cell proliferation and cancer progression. Herein, we report that ATAD2 directly interacts with TWIST1, and both N-terminal regions of proteins mediate the interaction. Immunofluorescence experiments suggested that ATAD2 and TWIST1 primarily colocalize in the nucleus. Notably, our qPCR results revealed the functional significance of ATAD2-TWIST1 interaction by demonstrating their synergistic effect on the transcriptional activation of MYC in colorectal carcinoma cell lines. Moreover, the ChIP-qPCR result further indicates that ATAD2 and TWIST1 significantly localize in the promoter of the MYC gene. In addition, analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data suggests a correlation between ATAD2, TWIST1, and MYC overexpression and poor survival rates in colorectal carcinoma. Lastly, the overexpression of ATAD2 and TWIST1 enhances cell proliferation, emphasizing their role in colorectal carcinoma progression through MYC activation. Together, these results suggest that ATAD2 is a crucial factor in TWIST1-dependent MYC gene activation, resulting in an active ATAD2-TWIST1-MYC axis that contributes to colon cancer cell proliferation.