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The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

ABSTRACT: Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at Chr12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development and loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit which can be used to support S-adenosyl methionine (SAM) synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.

INSTRUMENT(S): TSQ Quantiva

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Neil Kelleher

PROVIDER: MSV000085251 | MassIVE | Wed Apr 08 07:50:00 BST 2020

REPOSITORIES: MassIVE

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The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

Project description:Cancer cells are thought to adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here we show that the enzyme serine hydroxymethyltransferase-2 (SHMT2) is sufficient to initiate lymphoma development through a surprising epigenetic mechanism. This is relevant because SHMT2 localizes to the most frequent region of copy number gains Chr12q14.1 in lymphoma and other cancers. Physiologically, SHMT2 catalyzes the conversion of serine to glycine which yields activated methyl groups in the form of S-adenosyl methionine (SAM). A modest increase in the enzyme’s physiological function is both sufficient and required for lymphoma development. SHMT2 acts as a tumor initiator by inducing changes in DNA and histone methylation patterns. In particular, we observe promoter silencing of previously uncharacterized tumor suppressor genes that are also mutational targets in lymphoma, such as the scaffold protein SASH1 and the tyrosine phosphatase PTPRM. Together, our findings reveal that amplification of the wild type SHMT2 enzyme initiates lymphoma development through epigenetic tumor suppressor silencing.

2020-04-07 | GSE139523 | GEO

Small molecule activation of PKM in cancer cells induces serine auxotrophy

Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.

2012-12-20 | E-GEOD-40191 | biostudies-arrayexpress

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

Project description:The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing

| PRJNA580033 | ENA

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

Project description:The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

| PRJNA596658 | ENA

Small molecule activation of PKM in cancer cells induces serine auxotrophy

2012-12-20 | GSE40191 | GEO

Serine metabolism supports macrophage IL-1β production.

Project description:Serine is a substrate for nucleotides, NADPH and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage glutathione (GSH) synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1β mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1β levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1β cytokine production.

2019-01-15 | GSE125036 | GEO

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer

Project description:Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer

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Smallbone2013 - Serine biosynthesis

Project description:Smallbone2013 - Serine biosynthesis Kinetic modelling of metabolic pathways in application to Serine biosynthesis. This model is described in the article: Kinetic Modeling of Metabolic Pathways: Application to Serine Biosynthesis Kieran Smallbone, Natalie J. Stanford Methods in Molecular Biology. 2013; 985:113-121 Abstract: In this chapter, we describe the steps needed to create a kinetic model of a metabolic pathway using kinetic data from both experimental measurements and literature review. Our methodology is presented by using the example of serine biosynthesis in E. coli. As there are no plots to be reproduced as curation figure, table 6 and 7 that corresponds to steady state concentration of metabolite and steady state fluxes of reactions has been reproduced. This model is hosted on BioModels Database and identified by: BIOMD0000000458 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

2012-03-20 | BIOMD0000000458 | BioModels

Abberant Cathepsin S Activity Modulates the Immune Microenvironment in Follicular Lymphoma

Project description:Tumor cells can induce their own advantageous microenvironment. Here, we describe aberrant cathepsin S (CTSS) activity to modulate T-cell activation in follicular lymphoma (FL). In donor-derived FLs following bone marrow transplantation, we identified independent acquisition of CTSS mutations at Y132 in the donor´s and recipient's tumors. In a larger cohort, 6% of FL (20/312) harbored CTSS mutations, mostly Y132D, another 14% had CTSS amplification (40/280). Y132D leads to accelerated conversion from pro-CTSS to active CTSS and increased substrate cleavage, including CD74, which regulates MHC-II restricted antigen-presentation. In co-culture experiments, CTSS mutant lymphoma cells induced increased antigen-specific CD4+ T-cell activation. Moreover, antigen-processing was the top upregulated pathway in CTSS mutant primary FL biopsies. Thus, aberrant CTSS activity is a promising target in lymphoma.

2021-01-07 | PXD014612 | Pride

LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [RNA-seq]

Project description:Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.

2016-10-24 | GSE86144 | GEO

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