SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor

Sakamoto, Luís Carlos; Andrade, Rosângela Vieira de; Felipe, Maria Sueli Soares; Motoyama, Akira; Silva, Fábio Pittella

doi:10.1016/j.leukres.2014.01.013

Cited by 64 publications

(59 citation statements)

References 38 publications

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“…SMYD2 promotes cancer cell proliferation in head and neck squamous cell carcinoma and esophageal squamous-cell carcinoma [41,42], and overexpression of SMYD2 is a poor prognostic factor in pediatric acute lymphoblastic leukemia, gastric cancer and bladder cancer [40,43,44]. SMYD2 methylates H3K4 and H3K36 in vitro [106], and SMYD2-mediated H3K36me2 was reported to repress transcription of pro-inflammatory cytokines IL-6 and TNF-α in macrophages [107].…”

Section: Other H3k36 Methyltransferases: Smyd2 Setmar and Setd3mentioning

confidence: 99%

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H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Section: Other H3k36 Methyltransferases: Smyd2 Setmar and Setd3mentioning

confidence: 99%

“…The ASH1L KMTase is also overexpressed in cancer and regulates stem cell potential [7]. SMYD2 has oncogenic activity in multiple cancers [40][41][42][43][44], but whether this function depends on KMTase activity toward H3K36 or another of its many substrates is uncertain. …”

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H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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“…SMYD2 (SET and MYND domain 2) is a lysine methyltransferase (KMT) that has been implicated in cancer development. SMYD2 protein levels are elevated in various cancer types, and overexpression of SMYD2 in cancer cell lines promotes phenotypes associated with oncogenic transformation (Komatsu et al 2009(Komatsu et al , 2015Hamamoto et al 2014;Sakamoto et al 2014;Liu et al 2015). As a KMT, SMYD2 is a monomethyltransferase that was first thought to catalyze methylation of histone H3 at Lys36 (H3K36me) (Brown et al 2006), but it is unlikely that SMYD2 has this activity in cells.…”

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confidence: 99%

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.

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“…SMYD2 is highly expressed in 75% of esophageal squamous cell carcinomas (ESCCs) [57] and 95% of pediatric acute lymphoblastic leukemias [58] with poor survival. All of these characteristics point to its potential as a drug target to treat cancers.…”

Section: Smyd2mentioning

confidence: 99%

Histone lysine methyltransferases as anti-cancer targets for drug discovery

Liu

Wang

2016

Acta Pharmacol Sin

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Post-translational epigenetic modification of histones is controlled by a number of histone-modifying enzymes. Such modification regulates the accessibility of DNA and the subsequent expression or silencing of a gene. Human histone methyltransferases (HMTs) constitute a large family that includes histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs). There is increasing evidence showing a correlation between HKMTs and cancer pathogenesis. Here, we present an overview of representative HKMTs, including their biological and biochemical properties as well as the profiles of small molecule inhibitors for a comprehensive understanding of HKMTs in drug discovery.

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SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor

Cited by 64 publications

References 38 publications

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

Histone lysine methyltransferases as anti-cancer targets for drug discovery

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