SETD2: an epigenetic modifier with tumor suppressor functionality

Li, Jun; Duns, Gerben; Westers, Helga; Sijmons, Rolf H.; Berg, Anke van den; Kok, Klaas

doi:10.18632/oncotarget.9368

Cited by 145 publications

(138 citation statements)

References 120 publications

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“…46). Similarly, alterations of SETD2, another epigenetic modifier involved in transcription elongation, RNA processing, and DNA repair, plays an important role in maintaining genomic integrity, as observed in ccRCC (35). Therefore, SETD2 alterations may also contribute to the genomic instability of the 3p21 region in MM.…”

Section: Discussionmentioning

confidence: 99%

“…Alterations of SETD2, PBRM1, and SMARCC1 have been linked to several human malignancies (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37). PBRM1 is one of the most frequently mutated genes in ccRCC (31), and its alterations were also found in cholangiocarcinomas and liver cancers (38).…”

Section: Discussionmentioning

confidence: 99%

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High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Yoshikawa

Emi

Hashimoto-Tamaoki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

132

128

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We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable-SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Yoshikawa

Emi

Hashimoto-Tamaoki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

132

128

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“…1 SETD2 loss-of-function (LOF) mutations have been identified in various tumor types, indicating the tumor suppressor function of SETD2. 2–4 We previously identified about 6% of somatic SETD2 mutations in patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Moreover, SETD2 mutations were enriched in about 22% of MLL-rearranged (MLLr) leukemia patients.…”

Section: Introductionmentioning

confidence: 99%

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

Chen

Yan

et al. 2017

Leukemia

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Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusiontarget genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.

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“…In the context of the regulation of oncogenesis, the activity of STAT1 is either oncogenic or anti-oncogenic [10,11], and it may be that SETD2 contributes to the regulation of one, or both of these facets of STAT1 function. Also, given that SETD2 has been shown to have tumor suppressor activity [12], the SETD2-STAT axis discovered by Chen and colleagues may have some implications in the regulation of oncogenesis. In conclusion, the work by Chen and colleagues opens a new chapter in the intricate cytokine-STAT signaling pathways with clinical implications.…”

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confidence: 99%

Fine-tuning type I IFN signaling: A new chapter in the IFN saga

Yanai

Taniguchi

2017

Cell Res

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Type I interferon (IFN) signaling is critical for intracellular antimicrobial programmes, affecting both innate and adaptive immune responses. The paper recently published in Cell demonstrates a new regulatory mechanism of the type I IFN signaling pathway by histone-lysine N-methyltransferase SETD2.The Janus tyrosine kinase (JAK), Signal Transducer and Activator of Transcription (STAT) proteins, and Interferon Regulatory Factor (IRF) family of transcription factors are important mediators of many cytokine systems [1][2][3][4]. While cytokine research has impacted a number of fields, it is remarkable that the major cytokine pathways were first elucidated in the context of the same regulatory network, the type I interferon (IFN) system. As such, one may term the series of studies as a first wave of research on cytokine induction and action.The field may now be witnessing a so-called second wave of discovery related to how cytokine signaling systems are fine-tuned by other regulatory pathways. This is exemplified by a recent paper by Cao laboratory who demonstrate that type I IFN-induced STAT1 activation is regulated by histone-lysine N-methyltransferase SETD2 (SET domain containing 2), which has been previously characterized for its trimethylation of lysine 36 of histone H3 (H3K36) [5]. The authors first performed high-throughput screening of epigenetic modifiers by lentivirusmediated RNAi (RNA interference) to search for epigenetic factors that modu-

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SETD2: an epigenetic modifier with tumor suppressor functionality

Cited by 145 publications

References 120 publications

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

Fine-tuning type I IFN signaling: A new chapter in the IFN saga

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