Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming

Abstract

ObjectiveDespite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.DesignDNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.ResultsWe define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.ConclusionTogether our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF signaling in KMT2D Mutant Melanoma

“…The publically available CRISPR screening platform, Achilles (65), suggests a dependency of KMT2D mutant melanomas on specific genes in these other metabolic pathways which need further exploration. Indeed, a recent study suggested enhanced fatty acid metabolism in pancreatic cancer (53). Interestingly, the dependence of SMARCA4 mutant cancers on the blockade of oxidative phosphorylation was recently demonstrated (66) in lung cancer.…”

“…We observed that ~15% of melanoma cases identified harbored missense mutations in KMT2D whereas ~5%-8% of patients harbored missense mutations in KAT4 (Figures 2B and S2A) (35). As KMT2D mutations are prevalent (36-52) and this gene is increasingly reported to be a potential tumor suppressor across other tumor types (4)(5)(6)(7)36,53), we next sought to deeply characterize the mechanism of action of KMT2D in melanoma, particularly as the strongest phenotype in RNAi screen was seen with the KMT2D loss. A subset of the missense mutations in KMT2D were truncating or frameshift insertions/deletions (4.4%) that likely abrogates histone methyltransferase activity ( Figure 2B).…”

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

“…Dawkins and colleagues reported that reduced expression of KMT2D is associated with improved survival of PDAC patients 43 . However, a more recent study by Koutsioumpa and colleagues showed that low KMT2D expression increased proliferation and tumorigenicity in PDAC by altering glucose and lipid metabolism 44 . Our study showed that primary and metastatic PDACs had significantly lower expression of KMT2D and loss of KMT2D promoted PDAC invasion and migration, which supports a tumor-suppressive role of KMT2D in PDAC.…”

Ectopic HOTTIP Expression Induces Non-canonical Transactivation Pathways to Promote Growth and Invasiveness in Pancreatic Ductal Adenocarcinoma

“…Genome-wide analysis was performed using publicly available H3K4me3 (GSE85886) and HOXA13 (GSE49402) dataset and HOTTIP binding analysis by Triplex Domain Finder to identify genes with HOTTIP and H3K4me3 but not HOXA13 enrichment at their promoters (Fig. 4A) [14][15][16]. As expected, HOTTIP targets CYB5R2, SULT1A1, KIF26A, SLC1A4 and TSC22D1 were insensitive to HOXA13 knockdown ( Fig.…”