ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression

Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 08/2012; 122(9):3170-83. DOI: 10.1172/JCI63608
Source: PubMed


Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient's likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.

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Available from: Alexander Pertsemlidis
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    • "We and others showed that ectopic expression of miR-34 suppresses invasion and migration, which are processes required for metastasis, of colorectal, breast, liver, osteosarcoma, and lung cancer cells (Kim et al., 2011b; Mudduluru et al., 2011; Siemens et al., 2011; Dang et al., 2013; Yang et al., 2013b; Zhao et al., 2013b). The direct targets that mediate the suppression of cancer cell migration and invasion by miR-34 include the EMT-TF SNAIL (Kim et al., 2011b; Siemens et al., 2011), the RAS-oncogene homolog RRAS (Kaller et al., 2011), c-kit (Siemens et al., 2013a), Axl (Mackiewicz et al., 2011; Mudduluru et al., 2011), Arhgap1 (Ahn et al., 2012), PDGFR-a/b (Garofalo et al., 2013), Fra-1 (Wu et al., 2012; Yang et al., 2013b), and c-Met (Li et al., 2009a; Yan et al., 2012; Dang et al., 2013; Siemens et al., 2013b). Interestingly, c-Met is also directly repressed by p53 via the inhibition of SP1 binding to its promoter (Hwang et al., 2011). "
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    ABSTRACT: The tumor suppressor p53 is one of the most frequently mutated genes in human cancers. MicroRNAs (miRNAs) are small non-protein coding RNAs that regulate gene expression on the post-transcriptional level. Recently, it was shown that p53 regulates the expression of several miRNAs, thereby representing an important mechanism of p53 signaling. Several independent studies identified the members of the miR-34 family as the most prevalent p53-induced miRNAs. miR-34s are frequently silenced in variety of tumor entities, suggesting that they are important tumor suppressors. Indeed, ectopic expression of miR-34s inhibits proliferation, epithelial to mesenchymal transition, migration, invasion, and metastasis of various cancer cell entities. Moreover, delivery or re-expression of miR-34 leads to notable repression of tumor growth and metastasis in cancer mouse models, and may therefore represent an efficient strategy for future cancer therapeutics. Besides their crucial functions in cancer, members of the miR-34 family also play important roles in spermatogenesis, stem cell differentiation, neuronal development, aging, and cardiovascular functions. Consequently, miR-34 has also been implicated in various non-cancerous diseases, such as brain disorders, osteoporosis, and cardiovascular complications.
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    • "The miR-34 family acts on apoptosis and cell cycle through the repression of many proteins involved in the regulation of these two biological processes. In particular, the miR-34 family binds to the 3'-UTRs of genes such as CDK4 and CDK6 [50, 51] (cell cycle) [19], Bcl-2 [24, 52] (apoptosis), SNAIL [29, 32] (epithelial mesenchymal transition) [53] and CD44 (migration and metastasis) [54], and the miR-34 family thus represses their expression. A detailed list of miR-34 family targets is provided in Table 1. "
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    ABSTRACT: The mir-34 family was originally cloned and characterized in 2007 as a p53 target gene. Almost immediately it became clear that its major role is as a master regulator of tumor suppression. Indeed, when overexpressed, it directly and indirectly represses several oncogenes, resulting in an increase of cancer cell death (including cancer stem cells), and in an inhibition of metastasis. Moreover, its expression is deregulated in several human cancers. In 2013, a miR-34 mimic has become the first microRNA to reach phase 1 clinical trials. Here we review the miR-34 family and their role in tumor biology, and discuss the potential therapeutic applications of miR-34a mimic.
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    • "Given that MYB is a gene that positively autoregulates itself via tandem MYB binding sites located in the proximal promoter region [54], and that ZEB1 has been shown to inhibit the transcriptional activity of MYB [19], we propose that ZEB1 represses MYB gene expression by intercepting the positive-feedback cycle of MYB. ZEB1 downregulates miR34a in a similar manner by directly repressing the miR34a-positive transactivating protein, ΔNp63, resulting in the acquisition of invasive tumor cell capabilities [63]. "
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