去泛素化酶USP7调控ER阳性乳腺癌生长的分子机制研究

Estrogen receptor α（ERα）is a critical protein promoting the development and progression of breast cancer(BCa) and a crucial therapeutical target of BCa treatment. Currently, interfering the degradation of cellular oncoproteins has become an attractive anti-cancer strategy. Studies have shown that ERα is degraded through the Ubiquitin-proteasome system. However, it remains unknown whether deubiquitinases are involved in regulating ERα degradation. Ubiquitin specific protease 7 (USP7) is a well-documented member of deubiquitinases superfamily in eukaryotic cells. TCGA database shows that USP7 is highly expressed in BCa, especially in ERα+ BCa. Our previous studies showed that downregulation of USP7 not only notably suppressed the growth of ERα+ BCa, but also promoted the ubiquitin-mediated degradation of ERα which is associated with its deubiquitinase activity. Additionally, genetic or pharmacological inhibition of USP7 did not affect ERα mRNA level. Importantly, USP7 was highly expressed and positively related to the ERα protein level in ERα+ BCa. Therefore, we firstly propose that USP7 may regulate the growth of BCa via inhibiting ERα degradation. Depending on multiple level techniques, we will unravel the underlying mechanisms by which USP7 regulated the growth of BCa and hopefully provide a novel target for the diagnosis and treatment of BCa.

雌激素受体α（ERα）是促进乳腺癌发生发展的关键分子，也是治疗乳腺癌的重要靶点。干预细胞内癌蛋白降解已成为当前抗肿瘤的一种有效策略。研究表明，细胞中的ERα通过泛素蛋白酶体系统降解，但去泛素化酶是否参与调节ERα降解尚未见报道。USP7是真核细胞重要的去泛素化酶成员之一。TCGA数据库显示USP7在乳腺癌，尤其在ERα阳性乳腺癌高表达。我们前期研究发现：下调USP7的表达不仅明显抑制ERα阳性乳腺癌的生长，而且促进ERα的泛素化降解，这种作用与其去泛素化酶活性相关。其次，下调或抑制USP7并不明显影响ERα的mRNA表达。 重要的是， ERα阳性乳腺癌组织中USP7高表达，且与ERα的表达水平呈正相关。因此，我们首次提出：USP7可能通过抑制ERα的降解调控乳腺癌生长。本研究拟选取乳腺癌为研究对象，通过多种手段，多层次探究USP7调控乳腺癌生长的作用及其分子机制，为乳腺癌的诊治提供新靶点。

雌激素受体α（ERα）是促进乳腺癌发生发展的关键分子，也是治疗乳腺癌的重要靶点。 干预细胞内癌蛋白降解已成为当前抗肿瘤的一种有效策略。研究表明，细胞中的ERα通过泛素蛋白酶体系统降解，发现调控ERα蛋白稳定性的去泛素化酶具有重要意义。我们发现去泛素化酶USP7和USP15具有调控ERα泛素化降解的作用，并阐明了USP7和USP15调控ERα降解的分子机制。发现临床药物罗通定增加了ERα的泛素化水平，并促进其降解影响ERα阳性乳腺癌细胞生长。发现乳腺癌细胞HER2的表达受类泛素化修饰 Neddylation调控，从而改变其泛素化水平引起稳定性发生改变。发现抑制去泛素化酶USP14的活性可以在体内外增强恩杂鲁胺诱导的雄激素受体（AR）阳性乳腺癌细胞生长抑制。发现吴茱萸次碱可以通过促进雄激素受体剪切体（AR-V7）K48位泛素化选择性诱导其降解。综上所述，我们的研究证实了调控ERα蛋白稳定性的去泛素化酶及小分子药物，阐释了类泛素化修饰 Neddylation在HER2蛋白稳定性中的作用，并发现AR稳定性调控的新机制，为乳腺癌的诊治提供了新靶点。