Interferon-inducible protein IFIXalpha inhibits cell invasion by upregulating the metastasis suppressor maspin.
IFIXalpha, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIXalpha-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIXalpha. IFIXalpha 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 IFIXalpha. 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 IFIXalpha-expressing cells, IFIXalpha did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIXalpha-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIXalpha, suggesting that HDAC1 is regulated by IFIXalpha through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIXalpha.
Yamaguchi
Hirohito
H
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Ding
Yi
Y
Lee
Jin-Fong
JF
Zhang
Ming
M
Pal
Ashutosh
A
Bornmann
William
W
Yan
Duen-Hwa
DH
Hung
Mien-Chie
MC
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D009687:Nuclear Proteins; C487565:PYHIN1 protein, human; D012333:RNA, Messenger; C085344:SERPIN-B5; D015843:Serpins; D006655:Histone Deacetylases