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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE139523 | GEO | 2020/04/07

REPOSITORIES: GEO

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

Project description: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.

2020-04-08 | MSV000085251 | MassIVE

SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice

Project description:Non-alcoholic fatty liver disease is linked to disrupted serine metabolism. SHMT2 is a liver enzyme that is crucial for liver methylation and overall health. We developed a mouse strain with targeted SHMT2 knockout in hepatocytes and found that the absence of SHMT2 led to increased circulating serine and glycine levels, 1C deficiency, and depleted liver methylation potential. The study reveals the critical role of SHMT2 in maintaining hepatic 1C homeostasis and regulating the progression of non-alcoholic fatty liver disease.

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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

SHMT2 drives the progression of colorectal cancer by regulating UHRF1 expression

Project description:Introduction: Serine hydroxymethyltransferase 2 (SHMT2) has a critical role in serine-glycine metabolism to drive cancer cell proliferation. Yet, the function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Materials and Methods: CRC and paired normal samples were collected in the Department of Colorectal Surgery, XinHua Hospital, Shanghai Jiao Tong University School of Medicine and assessed by real-time polymerase chain reaction (qPCR) analysis, Western blot (WB), and immunohistochemistry (IHC). Moreover, SHMT2 expression in human CRC cells was identified by qPCR and WB. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown were explored through in vitro and in vivo assays. mRNA-seq assays were used to investigate the underlying mechanisms behind the SHMT2 function. Results: It was found that SHMT2 mRNA and protein were over-expressed in CRC tissue compared to the levels in normal mucosa. Positive expression of SHMT2 was significantly correlated with TNM stage and lymph node metastasis, and elevated expression of SHMT2 resulted as an independent prognostic factor in patients with CRC. SHMT2 knockdown impaired proliferation of CRC in vitro and in vivo and induced cell cycle arrest by regulating UHRF1 expression. Conclusion: Taken together, our findings reveal that UHRF1 is a novel target gene of SHMT2, which can be used as a potential therapeutic strategy for CRC therapy.

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Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer

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Proteomics and metabolomics reveal changes in cancer cells after alternation of SHMT2 expressions

Project description:In order to understand the underline mechanism of SHMT2 (serine hydroxymethyltransferase 2) effect on tumor growth, proteome and metabolome analysis were carried on a engineered HeLa cell line (HeLa-SHMT2-shSHMT2, short as HeLa-Ss), which has inducible SHMT2 over-expression or suppression by treating cell with tetracycline or IPTG, respectively. SHMT2 over-expression in HeLa-ss cell increased cell proliferation in vitro and in vivo, deceased expression of several mitochondrial complex I and III proteins, and increased glycine and glutathione levels in cells. BioID method identified more than 20 SHMT2 associated proteins that are involved in oxidation-reduction process. These results indicate SHMT2 involves in the regulation of cellular redox balance. SHMT2 repression only reduced growth of cells under glycine depletion condition. It increased expression of several proteins involved in glutaminolysis and amino acid transporters, and elevated metabolites related to glutamine metabolism. These results indicate tumor cells have a compensatory reaction after SHMT2 suppression. Further reducing glycine levels in cells by sodium benzoate caused cell death in cultured cell and slightly reduced tumor growth in vivo. Benzoate treatment induces more changes in protein expressions and metabolite levels and may be a new approach to inhibit tumor growth.

2020-08-19 | PXD004954 | Pride

Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer (2nd study)

Project description:The roles of the serine/glycine metabolic pathway (SGP) have recently been evident in certain types of tumor physiology; however, the pathological relevance of SGP in undifferentiated thyroid cancer remains unexplored. Herein, we employed a comparative transcriptome analysis of bulk RNA sequencing coupled with single-cell RNA sequencing, showing that the high expression of SHMT2 and MTHFD2 is tightly associated with a low thyroid differentiation score (TDS) and poor clinical features in thyroid cancer. In addition, unique metabolic reprogramming of SGP-relevant pathways in dedifferentiated cancer cells, and a distinct trajectory of a subpopulation of tumor cells with a high mitochondrial one-carbon pathway was observed. More importantly, such dramatic changes are functionally relevant, as inhibition of SHMT2 significantly compromises mitochondrial respiration and decreases tumor size by upregulating TDS markers. Taken together, our results highlight the importance of the mitochondrial one-carbon pathway, including SGP, in undifferentiated thyroid cancer and suggest that SHMT2 is a novel therapeutic target. RNA-seq data of 65 fresh frozen normal tissues were generated. Total RNA was isolated by RNeasy Mini Kit (Qiagen, CA, USA), according to the manufacturer's protocol. The quality and integrity of the RNA were confirmed by agarose gel electrophoresis and ethidium bromide staining, followed by visual examination under ultraviolet light. Sequencing library was prepared using TruSeq RNA Sample Preparation kit v2 (Illumina, CA, USA) according to the manufacturer’s protocols. Briefly, mRNA was purified from total RNA using poly-T oligo-attached magnetic beads, fragmented, and converted into cDNAs. Then, adapters were ligated and the fragments were amplified on a PCR. Sequencing was performed in paired end reads (2x75 bp) using NextSeq 500 platform (Illumina).

2024-07-01 | GSE223765 | GEO

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Project description:Mitochondria are cell’s powerhouses to provide energy and essential metabolic intermediates to ensure cellular functions, and its dysregulation plays an important role during tumorigenesis. Targeting mitochondria is a promising approach for cancer therapy. Glycyrrhetinic acid (GA) is a natural product with mitochondria-targeting property and shows broad anti-cancer activities, but its targets and underlying mechanisms remain elusive. Here we identify the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as a target of GA by using chemical proteomics. Binding to and inhibiting the catalytic activity of SHMT2 by GA are systematically validated in vitro and in vivo. Knockout of SHMT2 or inhibiting SHMT2 with GA restricts mitochondrial energy supplies through down-regulating mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation, and consequently suppresses cancer cell proliferation and tumor growth in xenograft mice. Crystal structures of GA derivatives indicate that GA can sit into folate-binding pocket of SHMT2 and regulate SHMT2 activity. Besides, chemical modifications at the carboxylic group of GA with diamines allows to significantly improve its anti-cancer potency, demonstrating GA as a decent structural template for SHMT2 inhibitor development. Collectively, these findings reveal the precise mechanism of action of GA that could be a promising drug lead for targeted therapies of certain cancers.

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Cancer proteome and metabolite changes linked to SHMT2

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