Functional Characterization of Nuclear Tyro3 in Colorectal Cancer Malignancy

Metastasis stands as the primary contributor to fatality across various cancers, including colorectal cancer (CRC). Nevertheless, the intricate mechanisms driving the advancement of metastasis remain shrouded in uncertainty. In a previous study, we divulged that matrix metalloproteinase-2 facilitates the liberation of the intracellular domain of TYRO3 (ICD-TYRO3), enabling its migration into the nucleus, thereby acting as a linchpin in the pathological processes’ characteristic of CRC. ICDTYRO3 propels cellular transformation in normal colon cells, encourages epithelial mesenchymal transition in CRC cells, and instigates metastasis in a mouse model designed to mimic the human condition. Through a proteomic analysis, bromodomain-containing protein 3 (BRD3), an epigenetic regulator that recognizes acetyl-lysine, emerged as one of the notable associates of nuclear TYRO3. This study embarks on an exploration of the functional roles played by nuclear TYRO3 and BRD3 in the context of CRC malignancy. Our findings demonstrate that nuclear TYRO3 exerts a protumorigenic influence by phosphorylating BRD3, thereby setting off processes such as epithelial mesenchymal transition, cell proliferation, and metastasis. The employment of a BRD3 inhibitor and the introduction of knockout techniques effectively curtail the functional capabilities of nuclear TYRO3, consequently tempering the pro-tumor characteristics displayed by CRC cells and impeding the metastatic potential of CRC in mice. These insights pave the way for potential therapeutic avenues in CRC treatment, focused on disrupting the translocation and operational role of nuclear TYRO3.