Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation

Park, Jin Woo; Kang, Joo-Young; Hahm, Ja Young; Kim, Hyun Jeong; Seo, Sang-Beom

doi:10.1038/s42003-020-01186-8

Cited by 8 publications

(7 citation statements)

References 39 publications

(48 reference statements)

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“…By immunoprecipitation of NSD2 protein and mass spectrum assay, we identified that the direct interaction between Aurora A and NSD2 could achieve the phosphorylation of NSD2 at serine 56 residue, and consequently improve its methyltransferase activity. Our data also indicated that phosphorylation of NSD2 at S56 suppressed both the degradation and cleavage of NSD2, which are critical for NSD2 protein stability and enzyme activity 38,39 . We identified that Aurora A‐mediated serine 56 phosphorylation of NSD2 plays critical role in cleavage and ubiquitination of NSD2, mainly through K11‐ and K29‐linked ubiquitin chains, in which K11‐linked ubiquitination leads to protein degradation, 40 and K29‐linked ubiquitination is responsible for protein‐protein interaction and degradation 41,42 .…”

Section: Discussionsupporting

confidence: 55%

“…Our data also indicated that phosphorylation of NSD2 at S56 suppressed both the degradation and cleavage of NSD2, which are critical for NSD2 protein stability and enzyme activity. 38 , 39 We identified that Aurora A‐mediated serine 56 phosphorylation of NSD2 plays critical role in cleavage and ubiquitination of NSD2, mainly through K11‐ and K29‐linked ubiquitin chains, in which K11‐linked ubiquitination leads to protein degradation, 40 and K29‐linked ubiquitination is responsible for protein‐protein interaction and degradation. 41 , 42 However, we couldn't define the causal consequence of cleavage and ubiquitination in the current study, which need further investigations.…”

Section: Discussionmentioning

confidence: 99%

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Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Jiang

Wang

et al. 2022

Clinical & Translational Med

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Background t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. Methods An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA‐seq. NSG mouse‐based xenograft model and intra‐bone model were applied to qualify the synergistic effect in vivo. Results We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain‐ and loss‐of‐functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ‐resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP‐1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. Conclusions Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Jiang

Wang

et al. 2022

Clinical & Translational Med

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“…1B , bottom). Our genomic screening assays identified multiple previously known dependencies of hematopoietic differentiation on a variety of genes such as METTL3, METTL14 and NSD2 ( Park et al, 2020 ; Vu et al, 2017 ; Weng et al, 2018 ) ( Fig. 1C , Supplementary Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Therefore, we investigated whether PIM1 would also act as a kinase for CBX8 during K562 cell differentiation. PIM1 is transcriptionally activated in response to hemin in K562 cells ( Park et al, 2020 ) ( Fig. 4A ).…”

Section: Resultsmentioning

confidence: 99%

Negative Regulation of Erythroid Differentiation via the CBX8-TRIM28 Axis

Kim

Park

Kang

et al. 2021

Molecules and Cells

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Although the mechanism of chronic myeloid leukemia (CML) initiation through BCR/ABL oncogene has been well characterized, CML cell differentiation into erythroid lineage cells remains poorly understood. Using CRISPR-Cas9 screening, we identify Chromobox 8 (CBX8) as a negative regulator of K562 cell differentiation into erythrocytes. CBX8 is degraded via proteasomal pathway during K562 cell differentiation, which activates the expression of erythroid differentiation-related genes that are repressed by CBX8 in the complex of PRC1. During the differentiation process, the serine/threonine-protein kinase PIM1 phosphorylates serine 196 on CBX8, which contributes to CBX8 reduction. When CD235A expression levels are analyzed, the result reveals that the knockdown of PIM1 inhibits K562 cell differentiation. We also identify TRIM28 as another interaction partner of CBX8 by proteomic analysis. Intriguingly, TRIM28 maintains protein stability of CBX8 and TRIM28 loss significantly induces proteasomal degradation of CBX8, resulting in an acceleration of erythroid differentiation. Here, we demonstrate the involvement of the CBX8-TRIM28 axis during CML cell differentiation, suggesting that CBX8 and TRIM28 are promising novel targets for CML research.

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“…NSD2 overexpression is linked with tumor aggressiveness [ 96 ] in cancers of the breast [ 97 ], cervix [ 98 ], lung [ 99 ], kidney [ 100 ], head and neck [ 101 ], brain [ 91 ], blood [ 102 ], colorectum [ 103 ], prostate, skin [ 96 ], and ovary [ 24 ]. Carcinogenesis associated with changes in the expression of NSD2 is also linked with cell cycle dysregulation [ 102 ], VEGF-A-mediated angiogenesis [ 104 ], hematopoietic stem cell differentiation [ 105 ], metastasis [ 91 ], chemoresistance (in osteosarcoma) [ 106 ], and the expression of various oncogenes (e.g., SYK , PTPN13 and ETV5 in multiple myeloma) [ 107 ]. Gain-of-function mutations (E1099K and T1150A) in the SET domain of NSD2 have been associated with the enhanced enzymatic activity of NSD2 in mantle cell lymphoma and pediatric acute lymphoblastic leukemia, in which they cause destabilization of the auto-inhibitory loop responsible for keeping signaling in check (refer below) [ 108 , 109 ].…”

Section: Histone H3k36 Di-methyl Transferasesmentioning

confidence: 99%

Structural and functional specificity of H3K36 methylation

Lam

Tan

Poh

et al. 2022

Epigenetics & Chromatin

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The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription, recombination, and DNA damage response. Loss- and gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders and various cancers. Structural analyses suggest that nucleosomal components such as the linker DNA and a hydrophobic patch constituted by histone H2A and H3 are likely determinants of H3K36 methylation in addition to the histone H3 tail, which encompasses H3K36 and the catalytic SET domain. Interaction of H3K36 methyltransferases with the nucleosome collaborates with regulation of their auto-inhibitory changes fine-tunes the precision of H3K36me in mediating dimethylation by NSD2 and NSD3 as well as trimethylation by Set2/SETD2. The identification of specific structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-(H3K36me2) and tri-(H3K36me3) methylated forms of H3K36, have highlighted the intricacy of H3K36me functional significance. Here, we consolidate these findings and offer structural insight to the regulation of H3K36me2 to H3K36me3 conversion. We also discuss the mechanisms that underlie the cooperation between H3K36me and other chromatin modifications (in particular, H3K27me3, H3 acetylation, DNA methylation and N6-methyladenosine in RNAs) in the physiological regulation of the epigenomic functions of chromatin.

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Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation

Cited by 8 publications

References 39 publications

Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Negative Regulation of Erythroid Differentiation via the CBX8-TRIM28 Axis

Structural and functional specificity of H3K36 methylation

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