ABSTRACT
We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation-phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA-protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2-4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Carcinoma, Squamous Cell , Pancreatic Neoplasms , Proteogenomics , Animals , Mice , Humans , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Biomarkers , Pancreatic NeoplasmsABSTRACT
Autophagy is a catabolic process through which cytoplasmic components are degraded and recycled in response to various stresses including starvation. Recently, transcriptional and epigenetic regulations of autophagy have emerged as essential mechanisms for maintaining homeostasis. Here, we identify that coactivator-associated arginine methyltransferase 1 (CARM1) methylates Pontin chromatin-remodeling factor under glucose starvation, and methylated Pontin binds Forkhead Box O 3a (FOXO3a). Genome-wide analyses and biochemical studies reveal that methylated Pontin functions as a platform for recruiting Tip60 histone acetyltransferase with increased H4 acetylation and subsequent activation of autophagy genes regulated by FOXO3a. Surprisingly, CARM1-Pontin-FOXO3a signaling axis can work in the distal regions and activate autophagy genes through enhancer activation. Together, our findings provide a signaling axis of CARM1-Pontin-FOXO3a and further expand the role of CARM1 in nuclear regulation of autophagy.
Subject(s)
ATPases Associated with Diverse Cellular Activities/metabolism , Autophagy/genetics , DNA Helicases/metabolism , Epigenesis, Genetic , Protein-Arginine N-Methyltransferases/metabolism , ATPases Associated with Diverse Cellular Activities/genetics , Acetylation , Animals , Arginine/metabolism , DNA Helicases/genetics , Fibroblasts , Forkhead Box Protein O3/metabolism , Gene Knockdown Techniques , Gene Knockout Techniques , Glucose/metabolism , HEK293 Cells , HeLa Cells , Hep G2 Cells , Histones/metabolism , Humans , Lysine Acetyltransferase 5/metabolism , Methylation , Mice, Transgenic , Protein Processing, Post-Translational , Protein-Arginine N-Methyltransferases/genetics , Signal Transduction/genetics , Trans-Activators/metabolism , Transcriptional ActivationABSTRACT
Autophagy is an essential process to maintain cell survival and homeostasis under various stress conditions. Here, we report that lysine-specific demethylase 3A (KDM3A) plays an important role in starvation-induced autophagy. Using Kdm3a knockout mice, we demonstrate that KDM3A is crucial for proper hepatic autophagy in vivo. Hepatic mRNA expression analysis and ChIP assay in WT and Kdm3a knockout mouse livers reveal that KDM3A activates autophagy genes by reducing histone H3K9me2 levels upon fasting. Together, our finding represents previously unidentified function of KDM3A as a key regulator of autophagy, implicating potential therapeutic approaches for autophagy-related diseases.
Subject(s)
Autophagy , Jumonji Domain-Containing Histone Demethylases/metabolism , Animals , Autophagosomes/metabolism , Fasting , Fibroblasts/metabolism , Gene Expression Regulation , Hep G2 Cells , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Liver/cytology , Liver/metabolism , Lysosomes/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Janus tyrosine kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2-STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2-STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2-STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2-STAT3 signaling pathway.
