SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma
SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma
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DOI：
10.1182/blood-2012-07-441022
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Yoshie, Osamu
中科院分区：
文献类型：
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作者：
Higuchi, Tomonori;Nakayama, Takashi;Yoshie, Osamu
以前，我们已经证明AP-1家族成员FRA-2在成人T细胞白血病/淋巴瘤（ATL）中组成性表达，并与JUND一起上调CCR 4并促进ATL细胞生长。FRA-2/JUND的潜在靶基因是SOX 4。在这里，我们研究SOX 4在ATL中的表达和功能。SOX 4确实在原代ATL细胞中一致表达。FRA-2/JUND通过AP-1位点有效激活SOX 4启动子。通过小干扰RNA（siRNA）敲低SOX 4表达强烈抑制ATL细胞系的细胞生长。微阵列分析显示，SOX 4敲低降低了诸如生发中心激酶相关（GCKR）、NAK相关蛋白1（NAP 1）和组蛋白脱乙酰酶8（HDAC 8）等基因的表达。我们证实了GCKR、NAP 1和HDAC 8在原代ATL细胞中的一致表达。我们还显示了SOX 4对HDAC 8启动子的直接激活。此外，GCKR、NAP 1和HDAC 8的siRNA敲低各自显著抑制ATL细胞系的细胞生长。总之，我们揭示了ATL中涉及FRA-2/JUND和SOX 4的重要致癌级联反应，其导致GCKR、NAP 1和HDAC 8等基因的表达。
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.