Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Kim, Jin Man; Kim, Kyung-Hwan; Schmidt, Thomas; Punj, Vasu; Tucker, Haley O.; Rice, Judd C.; Ulmer, Tobias S.; An, Woojin

doi:10.1093/nar/gkv874

Cited by 70 publications

(45 citation statements)

References 43 publications

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“…dCas9 fusion proteins have been successfully used in ESC and cancer cell lines to target a number of histone modifiers to specific genomic loci, including a histone demethylase (LSD1/KDM1A) (Kearns et al, 2015), a transcriptional coactivator and histone acetyltransferase (p300) (Hilton et al, 2015; Klann et al, 2017) and histone methyltransferases (SMYD3, PRDM9 and DOT1L) (Kim et al, 2015; Cano-Rodriguez et al, 2016; Kwon et al, 2017) (Fig. 1B).…”

Section: Cas9-mediated Chromatin Modificationsmentioning

confidence: 99%

“…When pursuing modification of specific chromatin marks, the use of the catalytic domain of the epigenetic effector protein, rather than the full-length protein itself, has been shown to be more efficient (Hilton et al, 2015; Kim et al, 2015; Choudhury et al, 2016; Liu et al, 2016; McDonald et al, 2016; Morita et al, 2016; Vojta et al, 2016; Xu et al, 2016; Stepper et al, 2017). Additionally, the majority of epigenetic engineering tools use amino acid linkers between the dCas9 protein and the effector domain to create a fusion protein.…”

Section: Technical Considerationsmentioning

confidence: 99%

“…This approach dramatically increases chromatin visualization and the efficiency of transcriptional expression and repression (Balboa et al, 2015; Ma et al, 2015; Pradeepa et al, 2016). Another strategy is to use multiple gRNAs that target a discrete DNA region in order to amplify the intended effect, as well as to promote epigenetic spreading of the targeted modification to adjacent chromatin (Maeder et al, 2013; Mali et al, 2013b; Hu et al, 2014; Hilton et al, 2015; Kim et al, 2015; Liu et al, 2016; McDonald et al, 2016; Morita et al, 2016; Pradeepa et al, 2016). A third strategy is based on the so-called SunTag system, an array of GCN4 peptide epitopes, separated by linker sequences attached to the dCas9 protein.…”

Section: Technical Considerationsmentioning

confidence: 99%

“…The strategies used to verify correct targeting are comprised of ChIP-seq against the dCas9 protein and the specific histone modifier, ChIP to detect the expected histone modification, and ChIP against other histone marks, along with ATAC-seq or DNase-Seq, to identify secondary chromatin alterations (Hilton et al, 2015; Kearns et al, 2015; Kim et al, 2015; Cano-Rodriguez et al, 2016). A complementary approach to validate the accuracy of dCas9-associated histone modifiers is to perform functional studies in vitro using purified dCas9 protein on recombinant histone octamers (Kim et al, 2015; Horlbeck et al, 2016b). …”

Section: Technical Considerationsmentioning

confidence: 99%

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CRISPR/Cas9-Based Engineering of the Epigenome

et al. 2017

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Determining causal relationships between distinct chromatin features and gene expression, and ultimately cell behavior, remains a major challenge. Recent developments in targetable epigenome-editing tools enables us to assign direct transcriptional and functional consequences to locus-specific chromatin modifications. This review discusses the unprecedented opportunity that CRISPR/(d)Cas9 technology offers for investigating and manipulating the epigenome to facilitate further understanding of stem cell biology and engineering of stem cells for therapeutic applications. We also provide technical considerations for standardization and further improvement of the CRISPR/(d)Cas9 tools.

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Section: Cas9-mediated Chromatin Modificationsmentioning

confidence: 99%

Section: Technical Considerationsmentioning

confidence: 99%

Section: Technical Considerationsmentioning

confidence: 99%

Section: Technical Considerationsmentioning

confidence: 99%

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CRISPR/Cas9-Based Engineering of the Epigenome

et al. 2017

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“…26, 27 Studies have reported that SUB1 interacts with distinct domains of activators such as VP16, GAL4, AP2, HIV-TAT, P53 and SMYD3 to modulate their functions. 19, 22, 28–32 Previous studies indicated that the overexpression of SUB1 in a population of normal dermal multipotent fibroblasts resulted in the tumorigenic transformation of the cells, indicating its role in tumorigenesis. SUB1 has been recently found to show an upregulated level in different cancers.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

et al. 2016

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MicroRNA-101, a tumor suppressor microRNA is often down-regulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2, COX2, POMP, CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that mir-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression. SUB1 is known to play diverse role in vital cell processes such as DNA replication, repair and heterochromatinization. SUB1 is known to modulate transcription and acts as a mediator between the upstream activators and general transcription machinery. Expression profiling in several cancers revealed SUB1 overexpression, suggesting a potential role in tumorigenesis. However, detailed regulation and function of SUB1 has not been elucidated. In this study, we show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Gene expression analyses coupled with chromatin immunoprecipitation revealed that SUB1 binds to the promoter regions of several oncogenes such as polo-like kinase PLK1, C-MYC, serine threonine kinase BUB1B and regulates their expression. Additionally, we observed SUB1 down-regulated CDKN1B expression. PLK1 knockdown or use of PLK1 inhibitor can mitigate oncogenic function of SUB1 in benign prostate cancer cells. Thus, our study suggests that miR-101 loss results in increased SUB1 expression and subsequent activation of known oncogenes driving prostate cancer progression and metastasis. This study therefore demonstrates functional role of SUB1 in the prostate cancer and identifies its regulation, and potential downstream therapeutic targets of SUB1 in prostate cancer.

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Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma

et al. 2017

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SMYD 3 is a member of the SET and myeloid‐Nervy‐DEAF‐1 (MYND) domain‐containing protein family of methyltransferases, which are known to play critical roles in carcinogenesis. Expression of SMYD 3 is elevated in various cancers, including esophageal squamous cell carcinoma (ESCC), and is correlated with the survival time of patients with ESCC . Here, we dissect gene expression data, from a previously described KYSE 150 ESCC cell line in which SMYD 3 had been knocked down, by integration with the protein–protein interaction ( PPI ) network, to find the new potential biological roles of SMYD 3 and subsequent target genes. By construction of a specific PPI network, differentially expressed genes ( DEG s), following SMYD 3 knockdown, were identified as interacting with thousands of neighboring proteins. Enrichment analyses from the DAVID Functional Annotation Chart found significant Gene Ontology ( GO ) terms associated with transcription activities, which were closely related to SMYD 3 function. For example, YAP 1 and GATA 3 might be a target gene for SMYD 3 to regulate transcription. Enrichment annotation of the total DEG PPI network by GO ‘Biological Process’ generated a connected functional map and found 532 significant terms, including known and potential biological roles of SMYD 3 protein, such as expression regulation, signal transduction, cell cycle, cell metastasis, and invasion. Subcellular localization analyses found that DEG s and their interacting proteins were distributed in multiple layers, which might reflect the intricate biological processes at the spatial level. Our analysis of the PPI network has provided important clues for future detection of the biological roles and mechanisms, as well as the target genes of SMYD 3.

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Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells

Cited by 70 publications

References 43 publications

CRISPR/Cas9-Based Engineering of the Epigenome

CRISPR/Cas9-Based Engineering of the Epigenome

MicroRNA-101 regulated transcriptional modulator SUB1 plays a role in prostate cancer

Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma

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