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LMTK3 Represses Tumour Suppressor-Like Genes through Chromatin Remodeling in Breast Cancer

ABSTRACT: LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer including breast, lung, gastric and colorectal. It is localized in different cellular compartments but its nuclear function has not been investigated thus far. We have mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB associated protein-1 (KAP1) as a novel binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1_, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumour suppressor-like genes. Furthermore, LMTK3 functions at enhancer regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a new model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling, revealing a new mechanism of RTK activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70385 | GEO | 2015/06/30

SECONDARY ACCESSION(S): PRJNA288494

REPOSITORIES: GEO

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Project description:We performed a genome-scale ChIP-chip comparison of two modifications (trimethylation of lysine 9 and trimethylation of lysine 27) of histone H3 in Ntera2 testicular carcinoma cells and in three different anatomical sources of primary human fibroblasts. We found that in each of the cell types the two modifications were differentially enriched at the promoters of the two largest classes of transcription factors. Specifically, zinc finger genes were bound by H3me3K9 and homeobox genes were bound by H3me3K27. We have previously shown that the PRC2 complex is responsible for mediating trimethylation of lysine 27 of histone H3 in human cancer cells. In contrast, there is little overlap between H3me3K9 targets and components of the PRC2 complex, suggesting that a different histone methyltransferase is responsible for the H3me3K9 modification. Previous studies have shown that SETDB1 can trimethylate H3 on lysine 9, using in vitro or artificial tethering assays. SETDB1 is thought to be recruited to chromatin by complexes containing the KAP1 co-repressor. To determine if a KAP1-containing complex mediates trimethylation of the identified H3me3K9 targets, we performed ChIP-chip assays and identified KAP1 target genes using human 5kb promoter arrays. We found that a large number of promoters of zinc finger transcription factors were bound by both KAP1 and H3me3K9 in normal and cancer cells. To expand our studies of KAP1, we next performed a complete genomic analysis of KAP1 binding using a 38 array tiling set, identifying ~7000 KAP1 binding sites. The identified KAP1 targets were highly enriched for C2H2 zinc fingers, especially those containing KRAB domains. Interestingly, although most KAP1 binding sites were within core promoter regions, the binding sites near ZNF genes were greatly enriched within transcribed regions of the target genes. Because KAP1 is recruited to the DNA via interaction with KRAB-ZNF proteins, we suggest that expression of KRAB-ZNF genes may be controlled via an auto-regulatory mechanism involving KAP1. Keywords: Human whole genome tiling array

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LMTK3 Represses Tumour Suppressor-Like Genes through Chromatin Remodeling in Breast Cancer

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