The transcription factor SP3 drives TNF- expression in response to Smac mimetics

Abstract

The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor- (TNF-) are important for immunity and its anticancer effects. Although chronic stimulation with TNF- is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF- signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-to-TNF-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF- by engaging the nuclear factor-B (NF-B) transcriptional pathway. Moreover, the promotion of TNF- expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF- production and signaling will help us further understand TNF- biology and provide insight into mechanisms relevant to cancer and inflammatory disease.