CapG promotes resistance to paclitaxel in breast cancer through transactivation of PIK3R1/P50
CapG promotes resistance to paclitaxel in breast cancer through transactivation of PIK3R1/P50
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CapG 通过 PIK3R1/P50 反式激活促进乳腺癌对紫杉醇的耐药性
DOI：
10.7150/thno.36338
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Wu, Jiong
中科院分区：
文献类型：
--
作者：
Chi, Yayun;Xue, Jingyan;Wu, Jiong
背景：化疗耐药是乳腺癌治疗中的一个主要问题，也是乳腺癌患者死亡的主要原因。化疗耐药性的生物标志物正在研究中。方法：建立紫杉醇耐药细胞，并进行RNA测序。进行了与两个额外的RNA-seq数据集组合的分析。采用免疫组化法研究了辅助化疗患者乳腺癌切除标本中CapG表达与病理反应和无病生存率的关系。通过半数最大抑制浓度（IC 50）和小鼠异种移植模型评估紫杉醇耐药性。结果如下：肌动蛋白结合蛋白CapG表达的增加与乳腺癌患者对紫杉醇化疗的耐药性密切相关，并降低了乳腺癌患者实现病理完全缓解的可能性。过表达CapG显著增强了乳腺癌细胞和异种移植肿瘤中的紫杉醇耐药性。在乳腺癌患者中，高CapG水平也与较短的无复发生存期以及PI 3 K/Akt信号转导的过度激活显著相关。从机制上讲，CapG增强PIK 3R 1表达，导致PI 3 K/Akt活化增加。出乎意料的是，CapG被发现与PIK 3R 1/P50的变体特异性启动子结合并直接增强其转录。我们还鉴定了p300/CBP作为CapG的转录辅助调节因子，其通过与CapG相互作用被募集到PIK 3R 1启动子，从而通过增强组蛋白H3 K27乙酰化来增加PIK 3R 1/P50转录。同样，抑制p300/CBP显著降低了PIK 3R 1/P50的CapG依赖性上调和随后的PI 3 K/Akt活化，导致乳腺癌细胞对紫杉醇治疗的敏感性增加。结论：高CapG水平可预测乳腺癌患者紫杉醇疗效差。靶向CapG介导的PI 3 K/Akt通路的过度激活可能减轻乳腺癌对化疗的耐药性。
Background: Chemotherapy resistance is a major problem in breast cancer treatment and a leading cause of mortality in breast cancer patients. Biomarkers for chemotherapy resistance is under investigation. Methods: Paclitaxel resistant cells were established and subjected to RNA sequencing. Analysis combined with two additional RNA-seq datasets was conducted. CapG expression in patients with adjuvant chemotherapy was studied in breast cancer resection specimens using IHC and related to pathological response and disease-free survival. Paclitaxel resistance was assessed by half-maximal inhibitory concentrations (IC50) and a mouse xenograft model. Results: Increased expression of actin-binding protein CapG strongly correlated with the resistance to paclitaxel chemotherapy and decreased probability to achieve pathological complete response in breast cancer patients. Overexpressing CapG significantly enhanced paclitaxel resistance in breast cancer cells and xenograft tumors. High CapG level also significantly correlated with shorter relapse-free survival as well as hyper-activation of PI3K/Akt signaling in breast cancer patients. Mechanistically, CapG enhanced PIK3R1 expression which led to increased PI3K/Akt activation. Unexpectedly, CapG was found to bind to the variant-specific promoter of PIK3R1/P50 and directly enhance its transcription. We also identified p300/CBP as a transcriptional coregulator of CapG, which is recruited to PIK3R1 promoter through interaction with CapG, thereby increasing PIK3R1/P50 transcription by enhancing histone H3K27 acetylation. Consistently, inhibiting p300/CBP substantially decreased CapG-dependent upregulation of PIK3R1/P50 and subsequent PI3K/Akt activation, resulting in increased sensitivity to paclitaxel treatment in breast cancer cells. Conclusion: High CapG levels may predict poor paclitaxel response in breast cancer patients. Targeting CapG-mediated hyperactivation of PI3K/Akt pathway may mitigate resistance to chemotherapy in breast cancer.