The Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2013 May 9;32(19):2493-8. doi: 10.1038/onc.2012.250. Epub 2012 Jun 25.
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.
SUMO 特异性蛋白酶 1（SENP1）是去 SUMO 化蛋白酶家族的成员，在调节雄激素受体依赖性转录和低氧信号转导中具有重要作用。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，我们已经在癌前前列腺上皮内瘤变（PIN）病变和来自患者的前列腺癌组织样本中检测到 SENP1 的过表达。虽然我们的全动物模型已经证明 SENP1 的诱导对于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不清楚。在这项研究中，我们通过分析超过 150 个前列腺癌标本，表明 SENP1 的表达与前列腺癌的侵袭性和复发直接相关。调节 SENP1 水平可控制前列腺癌细胞系的集落形成、裸鼠中的肿瘤生长，以及前列腺癌细胞的迁移和侵袭。在高转移性前列腺癌细胞中沉默 SENP1 水平会破坏它们向骨骼转移并引发继发性肿瘤的能力。从机制上讲，两种关键的骨重塑蛋白基质金属蛋白酶 2（MMP2）和 MMP9 的表达受 SENP1 通过 HIF1α 信号通路调节。所有这些结果都表明 SENP1 对前列腺癌进展的贡献，并表明 SENP1 可能是前列腺癌患者转移的预后标志物和治疗靶标。
