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Activation of LINE-1 antisense promoter stimulates the growth of cultured cells

ABSTRACT: Long interspersed element 1 (LINE-1, or L1) is a retrotransposon that constitutes ~17% of the human genome. Although ~6,000 full-length L1s spread throughout the human genome, their biological significance remains undetermined. L1 5’ untranslated region has a bidirectional promoter activity with a sense promoter, driving L1 mRNA, and an antisense promoter (ASP), driving L1-gene chimeric RNAs. Here, we stimulated L1 ASP activity using the CRISPR-Cas9 system to evaluate its biological impacts. Activation of L1 ASP enhances L1 retrotransposition and cell growth. Conversely, we identified epigallocatechin gallate (EGCG) as an inhibitor of L1 ASP. The inhibition of L1 ASP by EGCG decreased cell growth but did not affect L1 retrotransposition. Collectively, these results indicate that activation of L1 ASP activity fuels cell growth. To our knowledge, this is the first report demonstrating the role of L1 ASP in the biological process. Considering that L1 sequences are de-silenced in various tumor cells, activation of L1 ASP may be a cause of tumor growth and interfering with L1 ASP activity will be a potential strategy to suppress the growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152634 | GEO | 2020/12/22

REPOSITORIES: GEO

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Project description:Overexpression of the epidermal growth factor receptor family member Her-2/neu in breast cancer leads to autophosphorylation of the receptor, and induction of multiple downstream signaling pathways including Akt kinase to NF-ï«B cascade that is associated with poor prognosis. Previously, we demonstrated green tea polyhenol epigallocatechin 3-gallate (EGCG) inhibits growth of NF639 Her-2/neu-driven breast cancer cells via reducing receptor autophosphorylation, and downstream Akt and NF-ï«B activities (Pianetti et al., 2002). Interestingly, we noted that upon prolonged culture in the presence of EGCG some cells developed resistance to the polyphenol. Here we report that resistant cells have lost tyrosine phosphorylation on the Her-2/neu receptor. Surprisingly, they displayed elevated NF-ï«B activity, and inhibition of this activity sensitized cells to EGCG. Data from microarray analysis of the original and resistant NF639 populations of cells were subjected to Gene Set Enrichment Analysis (GSEA) pathway analysis, which revealed that the mitogen activated protein kinase (MAPK) pathway was activated in the resistant cells. Treatment of the resistant cells with a combination of EGCG and the MAPK inhibitor U0216 dramatically reduced colony growth and mesenchymal phenotype. Thus, activation of the MAPK pathway mediates resistance to EGCG. Our studies suggest that gene expression profiling of drug resistant cells may provide a mechanism of determining effective systemic therapies for treatment of these advanced cancers. Experiment Overall Design: Total RNA from original NF639 cells and EGCG resistant NF639 cells were harvested using the UltraspecII RNA isolation kit (Biotecx), following the manufacturerâs instruction. The RNA samples were submitted to Boston University Microarray Resource for microarray hybridization using Affymetrix Mouse 430A 2.0 chips. RNAs from two independent experiments were analyzed and data pooled for computational analysis.

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Activation of LINE-1 antisense promoter stimulates the growth of cultured cells

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