ITIH5, a p53-responsive gene, inhibits the growth and metastasis of melanoma cells by downregulating the transcriptional activity of KLF4.
ITIH5, a p53-responsive gene, inhibits the growth and metastasis of melanoma cells by downregulating the transcriptional activity of KLF4.
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ITIH5 是一种 p53 响应基因，通过下调 KLF4 的转录活性来抑制黑色素瘤细胞的生长和转移
DOI：
10.1038/s41419-021-03707-7
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发表时间：
2021-05-02
影响因子：
9
通讯作者：
Han C
中科院分区：
文献类型：
--
作者：
Liu J;Cao F;Li X;Zhang L;Liu Z;Li X;Lin J;Han C
ITIH 5是间-α-胰蛋白酶抑制（ITI）基因家族的成员，在许多癌症中作为假定的肿瘤抑制基因。然而，其在黑色素瘤中的作用和调节机制仍不清楚。在这里，我们发现ITIH 5的表达在黑色素瘤组织中与正常皮肤组织相比降低。ITIH 5表达降低与黑色素瘤患者的临床病理特征相关，并预测预后不良。ITIH 5的强制表达在体外和离体显著抑制黑素瘤细胞增殖和转移，而ITIH 5表达的敲低增强黑素瘤细胞的恶性行为。在进一步的机制研究中，我们发现p53可以直接结合ITIH 5的启动子，从而促进黑色素瘤细胞中ITIH 5的转录。此外，我们发现ITIH 5与Krüppel样因子4（KLF 4）相互作用并抑制其转录活性。总的来说，我们的数据不仅确定了ITIH 5在黑色素瘤中的肿瘤抑制作用，而且还揭示了p53上调ITIH 5可能通过下调KLF 4的转录活性来抑制黑色素瘤细胞的生长和迁移。
ITIH5, a member of the inter-α-trypsin inhibitory (ITI) gene family, acts as a putative tumour-suppressor gene in many cancers. However, its role and the regulatory mechanism in melanoma are still unclear. Here, we found that the expression of ITIH5 was decreased in melanoma tissues compared with normal skin tissues. Decreased expression of ITIH5 was correlated with clinicopathological features and predicted poor prognosis in patients with melanoma. Forced expression of ITIH5 significantly inhibited melanoma cell proliferation and metastasis in vitro and ex vivo while knockdown of ITIH5 expression enhanced the malignant behaviour of melanoma cells. In further mechanistic studies, we showed that p53 can directly bind to the promoter of ITIH5 and thus promotes transcription of ITIH5 in melanoma cells. Additionally, we found that ITIH5 interacted with Krüppel-like factor 4 (KLF4) and inhibited its transcriptional activity. Collectively, our data not only identified a tumour-suppressive role of ITIH5 in melanoma but also revealed that upregulation of ITIH5 by p53 suppressed melanoma cell growth and migration likely by downmodulating the transcriptional activity of KLF4.
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影响因子：
28.2
作者：
Kaur A;Ecker BL;Douglass SM;Kugel CH 3rd;Webster MR;Almeida FV;Somasundaram R;Hayden J;Ban E;Ahmadzadeh H;Franco-Barraza J;Shah N;Mellis IA;Keeney F;Kossenkov A;Tang HY;Yin X;Liu Q;Xu X;Fane M;Brafford P;Herlyn M;Speicher DW;Wargo JA;Tetzlaff MT;Haydu LE;Raj A;Shenoy V;Cukierman E;Weeraratna AT
通讯作者：
Weeraratna AT
影响因子：
82.9
作者：
Murgai M;Ju W;Eason M;Kline J;Beury DW;Kaczanowska S;Miettinen MM;Kruhlak M;Lei H;Shern JF;Cherepanova OA;Owens GK;Kaplan RN
通讯作者：
Kaplan RN
影响因子：
2.7
作者：
Huth, Sebastian;Huth, Laura;Baron, Jens Malte
通讯作者：
Baron, Jens Malte
影响因子：
37.3
作者：
Rose M;Kloten V;Noetzel E;Gola L;Ehling J;Heide T;Meurer SK;Gaiko-Shcherbak A;Sechi AS;Huth S;Weiskirchen R;Klaas O;Antonopoulos W;Lin Q;Wagner W;Veeck J;Gremse F;Steitz J;Knüchel R;Dahl E
通讯作者：
Dahl E
影响因子：
4.6
作者：
Rose, Michael;Meurer, Steffen K.;Dahl, Edgar
通讯作者：
Dahl, Edgar