Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target.
Benjamin M GreulichJoshua P PlotnikTravis J JerdePeter C HollenhorstPublished in: NAR cancer (2021)
The 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.
Keyphrases
- toll like receptor
- prostate cancer
- inflammatory response
- transcription factor
- nuclear factor
- immune response
- gene expression
- radical prostatectomy
- signaling pathway
- genome wide
- induced apoptosis
- electronic health record
- cell death
- poor prognosis
- dna methylation
- emergency department
- oxidative stress
- big data
- copy number
- dna binding
- single cell
- cell cycle arrest
- benign prostatic hyperplasia
- heat shock
- heat stress