Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.
Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.
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DOI：
10.1101/gad.241968.114
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发表时间：
2014-06-01
影响因子：
10.5
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Xu Y;Gao XD;Lee JH;Huang H;Tan H;Ahn J;Reinke LM;Peter ME;Feng Y;Gius D;Siziopikou KP;Peng J;Xiao X;Cheng C
这项研究揭示了一个剪接介导的途径，是乳腺癌转移所必需的。Cheng及其同事表明，RNA结合蛋白hnRNPM通过控制上皮-间充质转化（EMT）期间发生的选择性剪接促进乳腺癌转移。hnRNPM以细胞类型特异性的方式在EMT期间控制CD 44剪接和TGFβ信号传导。重要的是，hnRNPM与侵袭性乳腺癌相关，并与患者标本中CD 44增加相关。这些发现描绘了一种连接剪接调节和肿瘤转移的新机制。肿瘤转移仍然是癌症相关死亡的主要原因，但其分子基础仍不清楚。在这里，我们发现了一个剪接介导的途径，是乳腺癌转移所必需的。我们发现，RNA结合蛋白异质核核糖核蛋白M（hnRNPM）促进乳腺癌转移，激活开关的选择性剪接发生在上皮间质转化（EMT）。全基因组深度测序分析表明，hnRNPM增强TGFβ信号传导，并将CD 44鉴定为hnRNPM的关键下游靶标。hnRNPM消融防止TGFβ诱导的EMT并抑制小鼠中的乳腺癌转移，而特异性CD 44标准（CD 44 s）剪接同种型的强制表达覆盖hnRNPM的损失并允许EMT和转移。从机制上讲，我们证明了普遍表达的hnRNPM以间充质特异性方式精确控制EMT期间CD 44剪接异构体的转换。hnRNPM的这种受限制的细胞类型活性是通过与ESRP 1竞争实现的，ESRP 1是一种上皮剪接调节因子，与hnRNPM结合相同的顺式调节RNA元件，并在EMT期间被抑制。重要的是，hnRNPM与侵袭性乳腺癌相关，并与患者标本中CD 44的增加相关。这些发现证明了一种新的分子机制，通过这种机制，肿瘤转移是由hnRNPM介导的剪接程序赋予的。
This study uncovers a splicing-mediated pathway that is essential for breast cancer metastasis. Cheng and colleagues show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by controlling alternative splicing that occurs during the epithelial–mesenchymal transition (EMT). hnRNPM acts in a cell type-specific manner to control CD44 splicing and TGFβ signaling during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44 in patient specimens. The findings delineate a novel mechanism connecting splicing regulation and tumor metastasis. Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial–mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.
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