Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2′-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma

Gao, Xiao‐Ning; Zhao, Wugan; Wang, Guan‐Nan; Cui, Meiying; Zhang, Yang‐Rui; Li, Wencai

doi:10.3892/mmr.2015.4640

Cited by 5 publications

(6 citation statements)

References 26 publications

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“…Burkitt lymphoma is characterized by the deregulation of DNA methylation switching certain tumor suppressor genes off [26][27][28]. Serine biosynthesis pathway is linked to the methionine cycle, responsible for the production of S-adenosylmethionine (SAM), a universal methyl group donor in cellular DNA and histone methylation reactions.…”

Section: Nct-503 Decreases Histone and Dna Methylation And Causes Re-mentioning

confidence: 99%

Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Białopiotrowicz

Noyszewska‐Kania

Kachamakova‐Trojanowska

et al. 2020

Cancers

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Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.

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Section: Nct-503 Decreases Histone and Dna Methylation And Causes Re-mentioning

confidence: 99%

Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Białopiotrowicz

Noyszewska‐Kania

Kachamakova‐Trojanowska

et al. 2020

Cancers

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“…In various human tumor types such as acute and chronic leukemia [ 268 ], different malignant lymphomas [ 265 , 266 , 269 ], colorectal carcinoma [ 270 ], breast cancer [ 271 ] and gastric carcinoma [ 272 ], the tumor suppressor activity of Id4 is abrogated through epigenetic inactivation of its promoter by methylation during cancer development. These findings would suggest that Id4 gene methylation degree might be used as a tumor marker.…”

Section: The Role Of Id4 In Cancermentioning

confidence: 99%

The Id-protein family in developmental and cancer-associated pathways

2017

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Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases. Herein we provide an overview on the structural properties, mode of action, biological function and therapeutic potential of these regulatory proteins.

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“…In myeloid malignancies, ID4 acts as a tumour suppressor gene, and its inactivation by DNA methylation is associated with poor treatment outcome and overall survival [40]. In non-Hodgkin lymphoma, ID4 methylation inhibits apoptosis and promotes cell proliferation [30]. In prostate cancer, ID4 downregulation is by DNA methylation [41].…”

Section: Discussionmentioning

confidence: 99%

“…To narrow down candidate methylated genes in CSCC, we first identified 339 DEGs that contained DMCs in the promoter region and showed a negative correlation between gene expression and DNA methylation; 23 genes showed both DNA methylation and gene expression differences between CSCC and adjacent normal tissues. Of these 23 genes, two (ID4 and UCHL1) were not only associated with malignancy but could also be targeted by the demethylating agent azacitidine [30,31] (Fig. 2a) (Table S5).…”

Section: Identification Of Aberrantly Methylated Genes In Csccmentioning

confidence: 99%

UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes

Xia³

et al. 2020

EBioMedicine

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Background: Little is known about whether UVB can directly influence epigenetic regulatory pathways to induce cutaneous squamous cell carcinoma (CSCC). This study aimed to identify epigenetic-regulated signalling pathways through global methylation and gene expression profiling and to elucidate their function in CSCC development. Methods: Global DNA methylation profiling by reduced representation bisulfite sequencing (RRBS) and genome-wide gene expression analysis by RNA sequencing (RNA-seq) in eight pairs of matched CSCC and adjacent normal skin tissues were used to investigate the potential candidate gene(s). Clinical samples, animal models, cell lines, and UVB irradiation were applied to validate the mechanism and function of the genes of interest. Findings: We identified the downregulation of the TGF-b/BMP-SMAD-ID4 signalling pathway in CSCC and increased methylation of inhibitor of DNA binding/differentiation 4 (ID4). In normal human and mouse skin tissues and cutaneous cell lines, UVB exposure induced ID4 DNA methylation, upregulated DNMT1 and downregulated ten-eleven translocation (TETs). Similarly, we detected the upregulation of DNMT1 and downregulation of TETs accompanying ID4 DNA methylation in CSCC tissues. Silencing of DNMT1 and overexpression of TET1 and TET2 in A431 and Colo16 cells led to increased ID4 expression. Finally, we showed that overexpression of ID4 reduced cell proliferation, migration, and invasion, and increased apoptosis in CSCC cell lines and reduced tumourigenesis in mouse models. Interpretation: The results indicate that ID4 is downregulated by UVB irradiation via DNA methylation. ID4 acts as a tumour suppressor gene in CSCC development.

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Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2′-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma

Cited by 5 publications

References 26 publications

Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells

The Id-protein family in developmental and cancer-associated pathways

UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes

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