Abstract
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.
Highlights
Amplification of certain oncogenes can increase the expression of specific cancer mediators that participate in tumor progression and maintenance [1]
AU-rich element (ARE) play a major role in the post-transcriptional control of gene expression, which has been increasingly shown to be defective in cancer
Studying the effects of certain oncogene amplifications that frequently occur in cancer on the post-transcriptional control of ARE-mRNA is important
Summary
Amplification of certain oncogenes can increase the expression of specific cancer mediators that participate in tumor progression and maintenance [1]. They form homodimerization or heterodimerization of the receptor, and subsequent phosphorylation of the receptor domain c-terminal tyrosine residues occurs [4] These events lead to the activation of several intracellular signaling pathways that include the PI3K/AKT, PLCγ/protein kinase-C (PKC), Ras/MAPK/ERK, and JAK/STAT pathways [5, 6]. One target for MAPK pathway-stimulated phosphorylation is tristetraprolin (TTP, called ZFP36); it is an RNA-binding protein that generally promotes the decay of AU-rich mRNAs [12, 13]. When phosphorylated, it becomes inactive, leading to increased mRNA stability and enhanced translation [14, 15]. We intersected an updated list of 564 over-expressed breast cancer ARE-mRNAs based on our previous analysis [16] with a list
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