STAT1 represses Skp2 gene transcription to promote p27Kip1 stabilization in Ras-transformed cells.

The S-phase kinase-associated protein 2 (Skp2) is an F-box protein that serves as a subunit of the Skp1-Cullin-F-box ubiquitin protein ligase complex. Skp2 is overexpressed in many tumors and promotes tumor formation through its ability to induce the degradation of proteins with antiproliferative and tumor-suppressor functions, such as p27(Kip1). The signal transducer and activator of transcription 1 (STAT1) is a key regulator of the immune system through its capacity to act downstream of interferons. STAT1 exhibits tumor-suppressor properties by inhibiting oncogenic pathways and promoting tumor immunosurveillance. Previous work established the antitumor function of STAT1 in Ras-transformed cells through the induction of p27(Kip1) at the transcriptional level. Herein, we unveil a novel pathway used by STAT1 to upregulate p27(Kip1). Specifically, we show that STAT1 impedes Skp2 gene transcription by binding to Skp2 promoter DNA in vitro and in vivo. Decreased Skp2 expression by STAT1 is accompanied by the increased stability of p27(Kip1) in Ras-transformed cells. We further show that impaired expression of STAT1 in human colon cancer cells containing an activated form of K-Ras is associated with the upregulation of Skp2 and downregulation of p27(Kip1). Our study identifies Skp2 as a new target gene of STAT1 in Ras-transformed cells with profound implications in cell transformation and tumorigenesis.