Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways
Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways
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DOI：
10.15252/embr.201846078
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发表时间：
2019-02-01
期刊：
影响因子：
7.7
通讯作者：
Badve, Sunil S.
中科院分区：
文献类型：
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作者：
Gokmen-Polar, Yesim;Neelamraju, Yaseswini;Badve, Sunil S.
上皮剪接调节蛋白1和2 （ESRP1和ESRP2）控制癌症中上皮-间质转化（EMT）剪接程序。然而，它们在乳腺癌复发中的作用尚不清楚。在这项研究中，我们报道了高水平的ESRP1，而不是ESRP2，与雌激素受体阳性（ER+）乳腺肿瘤的不良预后相关。在内分泌耐药乳腺癌模型中，敲低ESRP1显著降低生长并改变EMT剪接特征，我们使用ER+ BRCA肿瘤的TCGA SpliceSeq数据证实了这一点。然而，这些变化并不伴随着间充质表型的发展或关键emt转录因子的变化。在他莫昔芬耐药细胞中，ESRP1的下调影响脂质代谢和氧化还原酶过程，导致脂肪酸合成酶（FASN）、硬脂酰辅酶a去饱和酶1 （SCD1）和磷酸甘油酸脱氢酶（PHGDH） mRNA和蛋白水平的表达降低。此外，ESRP1基因敲低增加了基础呼吸和备用呼吸能力。这项研究报告了ESRP1的一个新作用，它可能成为预防ER+乳腺癌他莫昔芬耐药的基础。
The epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) control the epithelial-to-mesenchymal transition (EMT) splicing program in cancer. However, their role in breast cancer recurrence is unclear. In this study, we report that high levels of ESRP1, but not ESRP2, are associated with poor prognosis in estrogen receptor positive (ER+) breast tumors. Knockdown of ESRP1 in endocrine-resistant breast cancer models decreases growth significantly and alters the EMT splicing signature, which we confirm using TCGA SpliceSeq data of ER+ BRCA tumors. However, these changes are not accompanied by the development of a mesenchymal phenotype or a change in key EMT-transcription factors. In tamoxifen-resistant cells, knockdown of ESRP1 affects lipid metabolism and oxidoreductase processes, resulting in the decreased expression of fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and phosphoglycerate dehydrogenase (PHGDH) at both the mRNA and protein levels. Furthermore, ESRP1 knockdown increases the basal respiration and spare respiration capacity. This study reports a novel role for ESRP1 that could form the basis for the prevention of tamoxifen resistance in ER+ breast cancer.