TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex that Drives Invasiveness of Gastric Adenocarcinoma

Abstract

Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, TRIM49, was identified as a potent suppressor of cancer invasiveness. In two-thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, where TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multi-organ metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely due to the failure to undergo TRIM49-mediated poly-ubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a pro-invasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying pro-invasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a pro-invasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles'heel that is potentially targetable to prevent metastasis.