Kinome-wide functional genomics screen reveals a novel mechanism of TNF?-induced nuclear accumulation of the HIF-1? transcription factor in cancer cells.

ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1?, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1? activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1? under normoxia conditions. TNF?, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1? activity. To improve our understanding of TNF?-mediated regulation of HIF-1? nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging-based HIF-1?-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNF? signaling (IKK/NF?B and JNK pathways) has no detrimental effect on HIF-1? accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNF? on HIF-1? stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NF?B signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNF? uses a distinct and complex signaling mechanism to induce accumulation of HIF-1? in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.

SUBMITTER: Schoolmeesters A 

PROVIDER: S-EPMC3280275 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature