Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication

Luís, A.; Vieira-Coimbra, Márcia; Vieira, Filipa Quintela; Costa-Pinheiro, Pedro; Silva-Santos, Rui; Dias, Paula C.; Antunes, Luís; Lobo, Francisco; Oliveira, Jorge; Gonçalves, Céline S.; Costa, Bruno M.; Henrique, Rui; Jerónimo, Carmen

doi:10.1080/15592294.2015.1103578

Cited by 55 publications

(42 citation statements)

References 51 publications

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“…Importantly, we have revealed that low SMYD2 expression predicted no-response of the AML patients to the standard induction chemotherapy. In line with our findings in AML, low levels of SMYD2 correlated with shorter survival in patients with renal cell carcinoma [69] and acquisition of complex karyotype and disease progression in chronic lymphocytic leukemia [70]. In other tumor types, including esophageal squamous cell carcinoma [31], gastric carcinoma [71], acute lymphoblastic leukemia (ALL) [72] and HPV-unrelated head and neck carcinoma [73], SMYD2 overexpression was associated with disease aggressiveness and worse outcome.…”

Section: Discussionsupporting

confidence: 90%

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

et al. 2017

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The molecular determinants governing escape of Acute Myeloid Leukemia (AML) cells from DNA damaging therapy remain poorly defined and account for therapy failures. To isolate genes responsible for leukemia cells regeneration following multiple challenges with irradiation we performed a genome-wide shRNA screen. Some of the isolated hits are known players in the DNA damage response (e.g. p53, CHK2), whereas other, e.g. SMYD2 lysine methyltransferase (KMT), remains uncharacterized in the AML context. Here we report that SMYD2 knockdown confers relative resistance to human AML cells against multiple classes of DNA damaging agents. Induction of the transient quiescence state upon SMYD2 downregulation correlated with the resistance. We revealed that diminished SMYD2 expression resulted in the upregulation of the related methyltransferase SET7/9, suggesting compensatory relationships. Indeed, pharmacological targeting of SET7/9 with (R)-PFI2 inhibitor preferentially inhibited the growth of cells expressing low levels of SMYD2.Finally, decreased expression of SMYD2 in AML patients correlated with the reduced sensitivity to therapy and lower probability to achieve complete remission. We propose that the interplay between SMYD2 and SET7/9 levels shifts leukemia cells from growth to quiescence state that is associated with the higher resistance to DNA damaging agents and rationalize SET7/9 pharmacological targeting in AML.

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Section: Discussionsupporting

confidence: 90%

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

et al. 2017

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“…SETD3 expression is lower in renal cell tumors than normal renal tissues, and low expression of SETD3 is associated with shorter survival in renal cell carcinoma patients [118]. SETD3 has been implicated in DNA replication and repair due to its interaction with proliferating cell nuclear antigen, a conserved factor involved in DNA synthesis [119].…”

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

“…(2016) 8(13) future science group Review Rogawski, Grembecka & Cierpicki SETD3 is a poorly characterized putative tumor suppressor that methylates H3K4 and H3K36 in vitro and in SETD3-transfected cells [117]. SETD3 expression is lower in renal cell tumors than normal renal tissues, and low expression of SETD3 is associated with shorter survival in renal cell carcinoma patients [118]. SETD3 has been implicated in DNA replication and repair due to its interaction with proliferating cell nuclear antigen, a conserved factor involved in DNA synthesis [119].…”

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confidence: 99%

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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“…Recent papers have also linked the expression of SETD3 to cancer progression. SETD3 was identified as novel biomarker for renal cell carcinoma (RCC)3: SETD3 expression was significantly higher in a set of RCC samples compared to normal renal tissues, and high expression of SETD3 was inversely correlated with disease-free survival3. In addition, it has been shown that a truncated version of SETD3 lacking the SET domain is highly expressed in lymphoma and that it displays oncogenic properties1.…”

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confidence: 99%

Chromatin associated SETD3 negatively regulates VEGF expression

Cohn

Feldman

Weil

et al. 2016

Sci Rep

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SETD3 is a member of the protein lysine methyltransferase (PKMT) family, which catalyzes the addition of methyl group to lysine residues. Accumulating data suggest that PKMTs are involved in the regulation of a broad spectrum of biological processes by targeting histone and non-histone proteins. Using a proteomic approach, we have identified 172 new SETD3 interacting proteins. We show that SETD3 binds and methylates the transcription factor FoxM1, which has been previously shown to be associated with the regulation of VEGF expression. We further demonstrate that under hypoxic conditions SETD3 is down-regulated. Mechanistically, we find that under basal conditions, SETD3 and FoxM1 are enriched on the VEGF promoter. Dissociation of both SETD3 and FoxM1 from the VEGF promoter under hypoxia correlates with elevated expression of VEGF. Taken together, our data reveal a new SETD3-dependent methylation-based signaling pathway at chromatin that regulates VEGF expression under normoxic and hypoxic conditions.

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Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication

Cited by 55 publications

References 51 publications

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

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

Chromatin associated SETD3 negatively regulates VEGF expression

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