title: SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma.
abstract: Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced the expression of genes such as germinal center kinase related (GCKR), NAK-associated protein 1 (NAP1), and histone deacetylase 8 (HDAC8). We confirmed consistent expression of GCKR, NAP1, and HDAC8 in primary ATL cells. We also showed direct activation of the HDAC8 promoter by SOX4. Furthermore, siRNA knockdown of GCKR, NAP1, and HDAC8 each significantly suppressed cell growth of ATL cell lines. Taken together, we have revealed an important oncogenic cascade involving FRA-2/JUND and SOX4 in ATL, which leads to the expression of genes such as GCKR, NAP1, and HDAC8.
authors.affiliation: Department of Microbiology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Higuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D051921:Fos-Related Antigen-2 / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D046228:Microarray Analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics*; D055751:SOXC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; C409470:HDAC8 protein, human; D006655:Histone Deacetylases