PSF Promotes ER-Positive Breast Cancer Progression via Posttranscriptional Regulation of ESR1 and SCFD2
PSF Promotes ER-Positive Breast Cancer Progression via Posttranscriptional Regulation of ESR1 and SCFD2
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DOI：
10.1158/0008-5472.can-19-3095
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发表时间：
2020-06-01
期刊：
影响因子：
11.2
通讯作者：
Inoue, Satoshi
中科院分区：
文献类型：
--
作者：
Mitobe, Yuichi;Iino, Kaori;Inoue, Satoshi
内分泌治疗是雌激素受体(ER)阳性乳腺癌的标准治疗方法，但长期治疗往往会引起获得性耐药，从而导致复发和转移。最近的研究表明，RNA结合蛋白(RBP)参与了肿瘤的发生。在这里，我们证明PSF/SFPQ是一种RBP，通过转录后调节ERα(ESR1)mRNA的表达来潜在地预测ER阳性乳腺癌患者的不良预后。在ER阳性乳腺癌患者中，强PSF免疫反应与较短的总生存期相关。PSF主要在对他莫昔芬耐药的乳腺癌细胞模型中表达，PSF的缺失抑制了培养细胞和异种移植瘤的增殖。PSF表达与雌激素信号转导显著相关。PSF siRNA通过抑制ESR1RNA的核输出而下调ESR1mRNA。微阵列和RNA免疫沉淀测序的综合分析也确定SCFD2、TRA2B和ASPM为PSF的靶标。在PSF靶点中，SCFD2是乳腺癌预后较差的指标，而SCFD2基因敲除显著抑制了乳腺癌细胞的增殖。综上所述，本研究表明PSF通过转录后调控其靶基因ESR1和SCFD2的表达，在ER阳性乳腺癌中发挥病理生理作用。总体而言，PSF和SCFD2可能成为原发性和激素抵抗型乳腺癌的潜在诊断和治疗靶点。意义：本研究确定了RNA结合蛋白PSF的致癌作用，该蛋白在ER阳性乳腺癌中具有转录后调节作用。
Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ER alpha (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.Significance: This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.