Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer

Nishikawaji, Taketo; Akiyama, Yoshimitsu; Shimada, Shu; Kojima, Kazuyuki; Kawano, Tatsuyuki; Eishi, Yoshinobu; Yuasa, Yasuhito; Tanaka, Shinji

doi:10.18632/oncotarget.11625

Cited by 26 publications

(16 citation statements)

References 41 publications

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“…Studies in patients with CLL with deletion of SETDB2 have shown an associated with disease progression [37]. A recently reported study showed that overexpression of SETDB2 may contribute to disease progression in gastric cancer [38]. These previous studies support the findings of the present study (Supplementary Table 5), and raise the possibility that CNAs function in tumorigenesis by several methods, regardless of their effects on gene expression.…”

Section: Discussionsupporting

confidence: 90%

Integrated Analysis of Genetic Abnormalities of the Histone Lysine Methyltransferases in Prostate Cancer

et al. 2019

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BackgroundThe histone methyltransferase (HMT) family includes histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs). The role of HMT gene variants in prostate cancer remains unknown. Therefore, this study aimed to evaluate HMT gene variants in the pathogenesis and prognosis of human prostate cancer, using in vitro cell studies and bioinformatics analysis.Material/MethodsIntegrative bioinformatics analysis of the expression of 51 HMT genes in human prostate cancer was based on datasets from the Cancer Genome Atlas (TCGA). Correlation and regression analysis were used to identify critical HMTs in prostate cancer. Kaplan-Meier and the area under the receiver operating characteristics curve (AUROC) were performed to evaluate the function of the HMTs on prognosis. Gene expression and function of 22Rv1 human prostate carcinoma cells were studied.ResultsThe HMT genes identified to have a role in the pathogenesis of prostate cancer included the EZH2, SETD5, PRDM12, NSD1, SETD6, SMYD1, and the WHSC1L1 gene. The EZH2, SETD5, and SMYD1 genes were selected as a prognostic panel, with the SUV420H2 HMT gene. SETD2, NSD1, and ASH1L were identified as critical genes in the development of castration-resistant prostate cancer (CRPC), similar to mixed-lineage leukemia (MLL) complex family members. Knockdown of the SETD5 gene in 22Rv1 prostate carcinoma cells in vitro inhibited cancer cell growth and migration.ConclusionsHMT gene variants may have a role in the pathogenesis of prostate cancer. Future studies may determine the role of HMT genes as prognostic biomarkers in patients with prostate cancer.

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Section: Discussionsupporting

confidence: 90%

Integrated Analysis of Genetic Abnormalities of the Histone Lysine Methyltransferases in Prostate Cancer

et al. 2019

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“…A potential role in cancer pathogenesis has been suggested by genomic sequencing studies (from The Cancer Genome Atlas; TCGA) revealing various mutations and copy number alterations of SETDB2 in a broad subset of cancers ( Figure S4D ). However, with the exception of a recent report characterizing the role of SETDB2 in a gastric cancer cell line ( Nishikawaji et al, 2016 ), there has been no functional link with oncogenesis. Our studies provide this by demonstrating that SETDB2 overexpression sustains leukemogenesis based on multiple lines of evidence, including mechanistic studies and clinical data.…”

Section: Discussionmentioning

confidence: 99%

“…However, most of these non-E2A-PBX1 cases do not display upregulation of CDKN2C following SETDB2 knockdown, suggesting oncogenic mechanisms based on alternative downstream target genes (data not shown). Indeed, the lack of overlap between SETDB2 targets identified in E2A-PBX1 + cells and those reported in mouse bone-marrow-derived macrophages ( Schliehe et al, 2015 ), or a gastric cancer cell line ( Nishikawaji et al, 2016 ), suggests that SETDB2 downstream targets are highly dependent on biological context, but the specific mechanisms for SETDB2 recruitment to the respective chromatin sites have not been determined. Furthermore, although SETDB2 has been shown to methylate substrate H3K9me2 peptide in vitro ( Falandry et al, 2010 ), a recent report showed that SETDB2 can positively regulate specific targets independent of its H3K9me3 methyltransferase activity ( Roqueta-Rivera et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression

et al. 2018

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SUMMARY Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL.

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“…SETDB2 plays important roles in immune system [15][16][17] and embryonic development [18,19]. In cancer research, SETDB2 has been found to be involved in cell cycle dysregulation in acute leukemia [20], associated with the prognosis and metastasis of renal tumors [21], and plays an oncogenic role in gastric cancer [22]. However, the roles and mechanism of SETDB2 in cancer stem cells and breast cancer are not clear.…”

Section: Ivyspringmentioning

confidence: 99%

SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein

Liu¹,

Xie²,

Jialun³

et al. 2020

Int. J. Biol. Sci.

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The histone H3K9 methyltransferase SETDB2 is involved in cell cycle dysregulation in acute leukemia and has oncogenic roles in gastric cancer. In our study, we found that SETDB2 plays essential roles in breast cancer stem cell maintenance. Depleted SETDB2 significantly decreased the breast cancer stem cell population and mammosphere formation in vitro and also inhibited breast tumor initiation and growth in vivo. Restoring SETDB2 expression rescued the defect in breast cancer stem cell maintenance. A mechanistic analysis showed that SETDB2 upregulated the transcription of the ΔNp63α downstream Hedgehog pathway gene. SETDB2 also interacted with and methylated ΔNp63α, and stabilized ΔNp63α protein. Restoring ΔNp63α expression rescued the breast cancer stem cell maintenance defect which mediated by SETDB2 knockdown. In conclusion, our study reveals a novel function of SETDB2 in cancer stem cell maintenance in breast cancer.

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Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer

Cited by 26 publications

References 41 publications

Integrated Analysis of Genetic Abnormalities of the Histone Lysine Methyltransferases in Prostate Cancer

Integrated Analysis of Genetic Abnormalities of the Histone Lysine Methyltransferases in Prostate Cancer

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression

SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein

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