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Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213647 | GEO | 2023/10/17

REPOSITORIES: GEO

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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).

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Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer

Project description:Mitochondrial SHMT2 is a crucial therapeutic target in dedifferentiated thyroid cancer

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

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

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

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