KMT2C Loss Promotes Small Cell Lung Cancer Metastasis through DNMT3A-mediated Epigenetic Reprogramming
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ABSTRACT:
PROVIDER: PRJNA678734 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13068213_1.fastq.gz | Fastqsanger.gz | |||
| SRR13068213_2.fastq.gz | Fastqsanger.gz | |||
| SRR13068214_1.fastq.gz | Fastqsanger.gz | |||
| SRR13068214_2.fastq.gz | Fastqsanger.gz | |||
| SRR13068215_1.fastq.gz | Fastqsanger.gz |
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Project description:Genes encoding the histone H3 lysine 4 (H3K4) methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinomas (PDAC). We examined the functional and transcriptional consequences of loss of these methyltransferases in patients with PDAC. Patients with low KMT2C and KMT2D expression demonstrated a much-improved outcome compared with those expressing high levels. RNA-seq analysis of KMT2C or KMT2D loss in three cell lines (PANC1, SUIT2 and COLO357) identified 31 and 124 differentially expressed genes respectively, with 19 genes common to both methlytransferases. Gene set enrichment analysis, and correlation with publicly available patient gene expression (GEP) datasets, highlighted significant reductions in pathways relating to cell-cycle and cell growth, where gene expression correlated with KMT2C/D depletion. Furthermore, loss of Kmt2d in three murine cell lines increased sensitivity to the nucleoside analogue 5-fluorouracil (5FU). These experiments support critical, non-redundant, roles for KMT2D and KMT2C in PDAC, where depletion impacts cell-cycle to reduce cell proliferation, enhance response to specific chemotherapy, which may improve patient survival.
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Project description:Histone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.
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Project description:Histone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.
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