SPDEF transcription factor shown to suppress prostate cancer
Prostate cancer continues to be the most common malignancy diagnosed in American men and the second leading cause of male cancer mortality.
Tanya Kalin, MD, PhD, leads a research team at Cincinnati Children’s that seeks to identify the direct role of several transcription factors (Foxm1, Foxf1, Foxf2, SPDEF) in prostate cancer. The team’s latest findings, published Sept. 25, 2014, in PLOS Genetics, explain how SPDEF transcription factor expression changes during prostate carcinogenesis, which suggests that new treatments could be developed that target Foxm1 via SPDEF dependent pathways.
“Our data demonstrate that SPDEF functions as a tumor suppressor in prostate cancers by inhibiting tumor cell proliferation via disruption of an auto-regulatory element in the Foxm1 promoter,” Kalin says. “It is possible that the loss of SPDEF causes increased expression of oncogenic Foxm1, accelerating tumor cell proliferation and leading to poor outcome in prostate cancer patients.”
Until now, researchers lacked useful transgenic mouse models to study the role of SPDEF in prostate cancer. Kalin and colleagues generated mice that either lacked or over-expressed SPDEF function. The mice revealed that loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro.
Specifically, over-expression of SPDEF inhibited RNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers, with the two-gene signature of low SPDEF and high Foxm1 predicting poor survival.
