Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation
Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation
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DOI：
10.1093/jb/mvx053
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发表时间：
2018-01-01
影响因子：
2.7
通讯作者：
Inoue, Satoshi
中科院分区：
文献类型：
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作者：
Okumura, Toshiyuki;Ikeda, Kazuhiro;Inoue, Satoshi
使用抗雌激素和芳香化酶抑制剂的内分泌疗法通常对治疗乳腺癌敏感的患者有效。然而，许多接受内分泌治疗的患者往往会产生耐药性。在本研究中，我们进行了功能筛选，利用短发夹RNA文库解剖基因参与抗雌激素他莫昔芬耐药的MCF-7乳腺癌细胞。我们根据临床数据集确定了7个与乳腺癌患者预后不良相关的候选基因。与亲本MCF-7细胞相比，在4-羟基他莫昔芬（OHT）抗性MCF-7（OHTR）细胞中，7个基因中的6个基因的表达水平更高。在6个选择的基因中，siRNA介导的PSMD 1和TSPAN 12的敲低显著降低了OHTR细胞的增殖。蛋白酶体26 S亚基PSMD 1基因的敲除可抑制p53蛋白的降解，从而抑制细胞周期的阻滞和p53蛋白的积累。与p53积累一致，其靶基因p21和SFN也被PSMD 1沉默上调。综上所述，PSMD 1被确定为在乳腺癌细胞中他莫昔芬耐药性的发展中起作用的潜在基因。这些发现将为内分泌治疗耐药的机制提供新的见解，并为晚期乳腺癌的预后和治疗提供分子靶点。
Endocrine therapy using antiestrogens and aromatase inhibitors is usually efficient to treat patients with hormone-sensitive breast cancer. Many patients with endocrine therapy, however, often acquire resistance. In the present study, we performed functional screening using short hairpin RNA library to dissect genes involved in antiestrogen tamoxifen resistance in MCF-7 breast cancer cells. We identified seven candidate genes that are associated with poor prognosis of breast cancer patients based on clinical dataset. The expression levels of six out of seven genes were higher in 4-hydroxytamoxifen (OHT) resistant MCF-7 (OHTR) cells compared with parental MCF-7 cells. Among the six selected genes, siRNA-mediated knockdown of PSMD1 and TSPAN12 markedly reduced the proliferation of OHTR cells. Notably, the knockdown of proteasome 26S subunit PSMD1 exhibited cell cycle arrest and the accumulation of p53 protein through inhibiting p53 protein degradation. In accordance with p53 accumulation, its target genes p21 and SFN were also upregulated by PSMD1 silencing. Taken together, PSMD1 was identified as a potential gene that plays a role in the development of tamoxifen resistance in breast cancer cells. These findings will provide a new insight for the mechanism underlying endocrine therapy resistance and a prognostic and therapeutic molecular target for advanced breast cancer.