Greulich, Benjamin M.Plotnik, Joshua P.Jerde, Travis J.Hollenhorst, Peter C.2022-05-182022-05-182021-01-27Greulich BM, Plotnik JP, Jerde TJ, Hollenhorst PC. Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target. NAR Cancer. 2021;3(1):zcaa046. Published 2021 Jan 27. doi:10.1093/narcan/zcaa046https://hdl.handle.net/1805/29054The TMPRSS2-ERG gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells. Our data confirm previous reports that ERG can transcriptionally activate TLR4 gene expression; however, using a constitutively active ERG mutant, we demonstrate that the critical function of TLR4 signaling is upstream, promoting ERG phosphorylation at serine 96 and ERG transcriptional activation. The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer.en-USAttribution 4.0 InternationalGene fusionProstate tumorsProstate cancer genomesTranscription factorsToll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic targetArticle