Methylation of Stat1 promoter can contribute to squamous cell carcinogenesis.

One of the most recently recognized signaling pathways that regulate tumor cell proliferation and survival involves signal transducers and activators of transcription (STAT) proteins. The STAT family of proteins has seven known members: Stat1, 2, 3, 4, 5A, 5B, and 6. Interestingly, it has become evident that dif ferent STAT proteins can serve either tumor suppressing or oncogenic roles. Stat1, for example, functions as a tumor suppressor in several capacities ( 1 – 5 ) , whereas Stat3 and to a lesser extent, Stat5, play a critical role in malignant progression at multiple levels ( 6 – 9 ) . Although it has been demonstrated that interferon-induced Stat1 activity can cause growth arrest and can induce apoptosis, it is not clear whether a lack of Stat1 in human cancer directly contributes to cancer cell proliferation and survival. If so, what keeps Stat1 from functioning in this manner in tumor cells also remains largely unknown. The article by Xi et al. ( 10 ) in this issue of the Journal presents evidence that Stat1 expression in squamous cell carcinoma of the head and neck (SCCHN) is lower than that of normal tissues from individuals without cancer. Restoring Stat1 expression in the tumor cells leads to growth inhibition in vitro and in xenograft tumors, which is accompanied by an increase in p21 expression. Their work further demonstrates that the low expression of Stat1 in SCCHN tumors is associated with Stat1 promoter methylation and that treatment with a methylation inhibitor increases STAT1 and p21 expression and sensitizes SCCHN tumor cells to cisplatin. These fi ndings are novel in several respects. Many independent studies, which involve mainly mouse tumor models or cell lines, have suggested that Stat1 can function as a tumor suppressor ( 1 – 5 ) . How does Stat1 function as a tumor suppressor? Stat1’s ability to mediate host immune defenses against tumors has been elegantly demonstrated in mice ( 2 ) . Increasing Stat1 activity by interferon treatment also leads to cell growth inhibition, which can be explained by Stat1’s capacity to induce p21waf and caspase expression ( 1 , 5 ) . Moreover, Stat1defi cient cells have defects both in S-phase and G 2 – M checkpoints in response to DNA damage ( 11 ) . Also, Stat1and p53-null mice show more frequent and rapid tumor development than wild-type mice. The basal expression level of the p53 inhibitor Mdm2 is higher in Stat1 − / − cells than in wild-type cells, suggesting that Stat1 is a negative regulator of Mdm2 expression ( 12 ) . The fi ndings by Xi et al. provide direct evidence supporting the