Interferon-inducible protein IFIXα inhibits cell invasion by upregulating the metastasis suppressor maspin

IFIX alpha, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIX alpha-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIX alpha. IFIX alpha suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIX alpha. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIX alpha-expressing cells, IFIX alpha did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIX alpha-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIX alpha, suggesting that HDAC1 is regulated by IFIX alpha through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIX alpha. (C) 2008 Wiley-Liss, Inc.