Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation
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ABSTRACT:
PROVIDER: PRJNA605406 | ENA |
REPOSITORIES: ENA
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Project description:Inhibiton of NSD2 by shRNA induces K562 differentiation via increasing erythroid specfic lineage factors The human myelogenous leukemic cell line, K562 undergoes erythroid differentiation by exposure to hemin. Here, we uncovered NSD2 as an innate erythroid differentiation-related factor through the genome-wide CRISPR library screening and explored the regulatory role of NSD2 during myeloid leukemia cell differentiation. We found that NSD2 stability was disrupted by poly-ubiquitination in differentiated K562 cells. Proteomic analysis revealed interaction between NSD2 and an E3 ubiquitin ligase, BRCA1 which ubiquitylates NSD K292 residue. Depletion of BRCA1 stabilized NSD2 protein and suppressed K562 cell differentiation. Furthermore, BRCA1 protein level was decreased in bone marrow tumor, while NSD2 level was elevated. Surprisingly, among BRCA1 mutation(s) discovered in lymphoma patients, BRCA1 K1183R prevented its translocation into the nucleus and did not reduce NSD2 protein level in hemin-treated K562 cells and eventually disrupted cell differentiation. Our results indicated that regulation of NSD2 stability by BRCA1-mediated ubiquitination as a potential therapeutic target process in multiple myeloma.
2020-03-25 | GSE144939 | GEO
Project description:The human myelogenous leukemic cell line, K562 undergoes erythroid differentiation by exposure to hemin. Here, we uncovered NSD2 as an innate erythroid differentiation-related factor through a genome-wide CRISPR library screen and explored the regulatory role of NSD2 during myeloid leukemia cell differentiation. We found that NSD2 stability was disrupted by poly-ubiquitination in differentiated K562 cells. Proteomic analysis revealed an interaction between NSD2 and an E3 ubiquitin ligase, BRCA1, which ubiquitylates NSD on K292. Depletion of BRCA1 stabilized NSD2 protein and suppressed K562 cell differentiation. Furthermore, BRCA1 protein level was decreased in bone marrow tumor, while NSD2 level was elevated. Surprisingly, among BRCA1 mutation(s) discovered in lymphoma patients, BRCA1 K1183R prevented its translocation into the nucleus, failed to reduce NSD2 protein levels in hemin-treated K562 cells and eventually disrupted cell differentiation. Our results indicate the regulation of NSD2 stability by BRCA1-mediated ubiquitination as a potential therapeutic target process in multiple myeloma.
| S-EPMC7443147 | biostudies-literature
Project description:NSD2 is a histone methyltransferase that specifically dimethylates histone H3 lysine 36 (H3K36me2), a modification associated with gene activation. Dramatic overexpression of NSD2 in t(4;14) multiple myeloma (MM) and an activating mutation of NSD2 discovered in acute lymphoblastic leukemia (ALL) are significantly associated with altered gene activation, transcription and DNA damage repair. The partner proteins through which NSD2 may influence critical cellular processes remain poorly defined. In this study, we utilized proximity-based labelling (BioID) combined with label-free quantitative mass spectrometry to identify high confidence NSD2 interacting partners in MM cells.
2019-06-27 | PXD013759 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-30 | PXD056679 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-30 | PXD056688 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-30 | PXD056645 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-30 | PXD056672 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-30 | PXD056676 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
2025-09-29 | PXD056689 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE29146: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP] GSE29147: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi] GSE29148: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO] GSE29150: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [Transduction] Refer to individual Series
2011-11-29 | E-GEOD-29305 | biostudies-arrayexpress