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Post-transcriptional screen of cancer amplified genes identifies ERBB2/Her2 signaling as AU-rich mRNA stability-promoting pathway
Oncogenesis ( IF 5.9 ) Pub Date : 2021-09-17 , DOI: 10.1038/s41389-021-00351-w
Jenan Al-Matouq 1, 2 , Latifa Al-Haj 1 , Maher Al-Saif 1 , Khalid S A Khabar 1
Affiliation  

Amplification of specific cancer genes leads to their over-expression contributing to tumor growth, spread, and drug resistance. Little is known about the ability of these amplified oncogenes to augment the expression of cancer genes through post-transcriptional control. The AU-rich elements (ARE)-mediated mRNA decay is compromised for many key cancer genes leading to their increased abundance and effects. Here, we performed a post-transcriptional screen for frequently amplified cancer genes demonstrating that ERBB2/Her2 overexpression was able to augment the post-transcriptional effects. The ERBB1/2 inhibitor, lapatinib, led to the reversal of the aberrant ARE-mediated process in ERBB2-amplified breast cancer cells. The intersection of overexpressed genes associated with ERBB2 amplification in TCGA datasets with ARE database (ARED) identified ERBB2-associated gene cluster. Many of these genes were over-expressed in the ERBB2-positive SKBR3 cells compared to MCF10A normal-like cells, and were under-expressed due to ERBB2 siRNA treatment. Lapatinib accelerated the ARE-mRNA decay for several ERBB2-regulated genes. The ERBB2 inhibitor decreased both the abundance and stability of the phosphorylated inactive form of the mRNA decay-promoting protein, tristetraprolin (ZFP36/TTP). The ERBB2 siRNA was also able to reduce the phosphorylated ZFP36/TTP form. In contrast, ectopic expression of ERBB2 in MCF10A or HEK293 cells led to increased abundance of the phosphorylated ZFP36/TTP. The effect of ERBB2 on TTP phosphorylation appeared to be mediated via the MAPK-MK2 pathway. Screening for the impact of other amplified cancer genes in HEK293 cells also demonstrated that EGFR, AKT2, CCND1, CCNE1, SKP2, and FGFR3 caused both increased abundance of phosphorylated ZFP36/TTP and ARE-post-transcriptional reporter activity. Thus, specific amplified oncogenes dysregulate post-transcriptional ARE-mediated effects, and targeting the ARE-mediated pathway itself may provide alternative therapeutic approaches.



中文翻译:

癌症扩增基因的转录后筛选将 ERBB2/Her2 信号识别为富含 AU 的 mRNA 稳定性促进途径

特定癌症基因的扩增导致它们的过度表达,从而导致肿瘤生长、扩散和耐药性。人们对这些扩增的癌基因通过转录后控制增强癌基因表达的能力知之甚少。富含 AU 的元素 (ARE) 介导的 mRNA 衰变对许多关键癌症基因造成损害,导致它们的丰度和影响增加。在这里,我们对频繁扩增的癌症基因进行了转录后筛选,证明 ERBB2/Her2 过表达能够增强转录后效应。ERBB1/2 抑制剂拉帕替尼可逆转 ERBB2 扩增的乳腺癌细胞中异常的 ARE 介导过程。TCGA 数据集中与 ERBB2 扩增相关的过表达基因与 ARE 数据库 (ARED) 的交集确定了 ERBB2 相关基因簇。与 MCF10A 正常样细胞相比,许多这些基因在 ERBB2 阳性 SKBR3 细胞中过度表达,并且由于 ERBB2 siRNA 处理而表达不足。拉帕替尼加速了几个 ERBB2 调节基因的 ARE-mRNA 衰变。ERBB2 抑制剂降低了 mRNA 衰变促进蛋白三四脯氨酸 (ZFP36/TTP) 的磷酸化非活性形式的丰度和稳定性。ERBB2 siRNA 也能够减少磷酸化的 ZFP36/TTP 形式。相反,ERBB2 在 MCF10A 或 HEK293 细胞中的异位表达导致磷酸化 ZFP36/TTP 的丰度增加。ERBB2 对 TTP 磷酸化的影响似乎是通过 MAPK-MK2 通路介导的。筛选 HEK293 细胞中其他扩增的癌症基因的影响也表明 EGFR、AKT2、CCND1、CCNE1、SKP2 和 FGFR3 导致磷酸化 ZFP36/TTP 和 ARE 转录后报告基因活性的丰度增加。因此,特定扩增的致癌基因失调了转录后 ARE 介导的效应,并且靶向 ARE 介导的途径本身可能提供替代治疗方法。

更新日期:2021-09-17
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