ATAD2 and TWIST1 Interaction Promotes MYC Activation\nin Colorectal Carcinoma

ATPase\nfamily AAA domain-containing protein 2 (ATAD2) is significantly\nup-regulated in many cancer types and contributes to poor patient\noutcomes. ATAD2 exhibits a multidomain architecture comprising an\nN-terminal acidic domain, two AAA+ ATPase domains, a bromodomain,\nand a C-terminal domain. The AAA+ ATPase domain facilitates protein\noligomerization and ATP binding, while the bromodomain recognizes\nacetylated lysine in histones and nonhistone proteins. ATAD2 involvement\nin cancer extends across multiple signaling pathways, such as Rb-E2F1,\nPI3K/AKT, and TGF-β1/Smad3, which promotes cell proliferation\nand cancer progression. Herein, we report that ATAD2 directly interacts\nwith TWIST1, and both N-terminal regions of proteins mediate the interaction.\nImmunofluorescence experiments suggested that ATAD2 and TWIST1 primarily\ncolocalize in the nucleus. Notably, our qPCR results revealed the\nfunctional significance of ATAD2–TWIST1 interaction by demonstrating\ntheir synergistic effect on the transcriptional activation of MYC\nin colorectal carcinoma cell lines. Moreover, the ChIP-qPCR result\nfurther indicates that ATAD2 and TWIST1 significantly localize in\nthe promoter of the <i>MYC</i> gene. In addition, analysis\nof The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis\nConsortium (CPTAC) data suggests a correlation between ATAD2, TWIST1,\nand MYC overexpression and poor survival rates in colorectal carcinoma.\nLastly, the overexpression of ATAD2 and TWIST1 enhances cell proliferation,\nemphasizing their role in colorectal carcinoma progression through\nMYC activation. Together, these results suggest that ATAD2 is a crucial\nfactor in TWIST1-dependent <i>MYC</i> gene activation, resulting\nin an active ATAD2-TWIST1-MYC axis that contributes to colon cancer\ncell proliferation.