SUMO-specific protease 1 promotes prostate cancer progression and metastasis
SUMO-specific protease 1 promotes prostate cancer progression and metastasis
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SUMO特异性蛋白酶1促进前列腺癌进展和转移
DOI：
10.1038/onc.2012.250
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发表时间：
2013-05-09
期刊：
影响因子：
8
通讯作者：
Cheng, J.
中科院分区：
文献类型：
--
作者：
Wang, Q.;Xia, N.;Cheng, J.
sumo特异性蛋白酶1 （SENP1）是去sumo化蛋白酶家族的成员，在雄激素受体依赖性转录和缺氧信号的调控中起重要作用。SENP1的这种活性谱促使我们研究SENP1是否参与前列腺癌的发病机制。在之前的研究中，我们检测到了SENP1在癌前前列腺上皮内瘤变（PIN）病变和前列腺癌组织样本中的过表达。尽管我们的全动物模型已经证明SENP1诱导对前列腺细胞转化至关重要，但SENP1在前列腺癌进展中的作用仍然未知。在这项研究中，我们通过分析150多个前列腺癌标本，发现SENP1的表达与前列腺癌的侵袭性和复发直接相关。SENP1水平的调节决定了前列腺癌细胞的集落形成、裸鼠肿瘤的生长以及前列腺癌细胞的迁移和侵袭。沉默高转移性前列腺癌细胞中的SENP1水平会扰乱其骨转移能力并引发继发性肿瘤。从机制上讲，两种关键骨重塑蛋白基质金属蛋白酶2 （MMP2）和MMP9的表达是由SENP1通过HIF1α信号通路调节的。这些结果表明SENP1在前列腺癌的发展过程中发挥了重要作用，提示SENP1可能是前列腺癌患者预后的标志物和转移的治疗靶点。
SUMO-specific protease 1 (SENP1) is a member of de-SUMOylation protease family and has an important role in the regulation of androgen receptor-dependent transcription and hypoxia signaling. This activity profile of SENP1 prompted us to investigate whether SENP1 is involved in the pathogenesis of prostate cancer. In previous studies, we have detected the overexpression of SENP1 in both precancerous prostate intraepithelial neoplasia (PIN) lesions and prostate cancer tissue samples from patients. Whereas our whole-animal model has demonstrated that SENP1 induction is critical for prostate cell transformation, the role of SENP1 in prostate cancer progression is still unknown. In this study, we show that SENP1 expression directly correlates with prostate cancer aggressiveness and reccurrence, by analyzing more than 150 prostate cancer specimens. Modulating SENP1 level dictates colony formation of prostate cancer cell lines, tumor growth in nude mice and also prostate cancer cell migration and invasion. Silencing SENP1 level in highly metastatic prostate cancer cells perturbs their ability to metastasize to the bone and initiates secondary tumors. Mechanistically, the expression of two critical bone remodeling proteins, matrix metalloproteinase 2 (MMP2) and MMP9, is regulated by SENP1 through the HIF1α signaling pathway. All these results show the contribution of SENP1 to the progression of prostate cancer, and suggest that SENP1 may be a prognostic marker and a therapeutic target for metastasis in prostate cancer patients.