PLU1 histone demethylase decreases the expression of KAT5 and enhances the invasive activity of the cells

2011 ◽  
Vol 437 (3) ◽  
pp. 555-564 ◽  
Author(s):  
Masakazu Yoshida ◽  
Akihiko Ishimura ◽  
Minoru Terashima ◽  
Zanabazar Enkhbaatar ◽  
Naohito Nozaki ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Histone H3 ◽  
Ectopic Expression ◽  
Histone Demethylase ◽  
Invasive Cancer ◽  
Invasive Potential ◽  
Demethylase Activity ◽  
Candidate Oncogene

PLU1 is a candidate oncogene that encodes H3K4 (Lys4 of histone H3) demethylase. In the present study, we found that ectopic expression of PLU1 enhanced the invasive potential of the weakly invasive cells dependent on its demethylase activity. PLU1 was shown to repress the expression of the KAT5 gene through its H3K4 demethylation on the promoter. The regulation of KAT5 by PLU1 was suggested to be responsible for PLU1-induced cell invasion. First, knockdown of KAT5 similarly increased the invasive potential of the cells. Secondly, knockdown of PLU1 in the highly invasive cancer cells increased KAT5 expression and reduced the invasive activity. Thirdly, simultaneous knockdown of KAT5 partially relieved the suppression of cell invasion imposed by PLU1 knockdown. Finally, we found that CD82, which was transcriptionally regulated by KAT5, might be a candidate effector of cell invasion promoted by PLU1. The present study demonstrated a functional contribution of PLU1 overexpression with concomitant epigenetic dysregulation in cancer progression.

scholarly journals LSD1: more than demethylation of histone lysine residues

2020 ◽  
Vol 52 (12) ◽  
pp. 1936-1947
Author(s):  
Bruno Perillo ◽  
Alfonso Tramontano ◽  
Antonio Pezone ◽  
Antimo Migliaccio
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Regulation Of Gene Expression ◽  
Histone H3 ◽  
Histone Demethylase ◽  
Special Role ◽  
Histone H4 ◽  
Nonhistone Proteins ◽  
Lysine Residues ◽  
Demethylase Activity

AbstractLysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.

scholarly journals KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer

2016 ◽  
Vol 10 ◽  
pp. BCBCR.S40182 ◽  
Author(s):  
Jeison Garcia ◽  
Fernando Lizcano
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Chromosome Segregation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Human Cancer ◽  
Histone Demethylase ◽  
Breast Cancer Cell Lines ◽  
Demethylase Activity

The Jumonji-containing domain protein, KDM4C, is a histone demethylase associated with the development of several forms of human cancer. However, its specific function in the viability of tumoral lineages is yet to be determined. This work investigates the importance of KDM4C activity in cell proliferation and chromosome segregation of three triple-negative breast cancer cell lines using a specific demethylase inhibitor. Immunofluorescence assays show that KDM4C is recruited to mitotic chromosomes and that the modulation of its activity increases the number of mitotic segregation errors. However, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell proliferation assays demonstrate that the demethylase activity is required for cell viability. These results suggest that the histone demethylase activity of KDM4C is essential for breast cancer progression given its role in the maintenance of chromosomal stability and cell growth, thus highlighting it as a potential therapeutic target.

scholarly journals Cadmium Induces Histone H3 Lysine Methylation by Inhibiting Histone Demethylase Activity

2015 ◽  
Vol 145 (1) ◽  
pp. 80-89 ◽  
Author(s):  
Chunlian Xiao ◽  
Yin Liu ◽  
Chengfeng Xie ◽  
Wei Tu ◽  
Yujie Xia ◽  
...  
Keyword(s):  
Histone H3 ◽  
Histone Demethylase ◽  
Lysine Methylation ◽  
Demethylase Activity

scholarly journals Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mingxuan Wu ◽  
Dawn Hayward ◽  
Jay H Kalin ◽  
Yun Song ◽  
John WR Schwabe ◽  
...  
Keyword(s):  
Hydroxamic Acid ◽  
Histone H3 ◽  
Intrinsic Property ◽  
Histone Demethylase ◽  
Enzyme Complex ◽  
The Core ◽  
Marked Preference ◽  
Steric Accessibility ◽  
Demethylase Activity ◽  
Enzymatic Complex

The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

scholarly journals Histone Demethylase LSD1 Regulates Kidney Cancer Progression by Modulating Androgen Receptor Activity

2020 ◽  
Vol 21 (17) ◽  
pp. 6089
Author(s):  
Kyoung-Hwa Lee ◽  
Byung-Chan Kim ◽  
Seung-Hwan Jeong ◽  
Chang Wook Jeong ◽  
Ja Hyeon Ku ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Cancer Cells ◽  
Kidney Cancer ◽  
Cancer Progression ◽  
Methylation Status ◽  
Histone Demethylase ◽  
New Drugs ◽  
Gene Promoters ◽  
Mesenchymal Transition ◽  
Knock Down

Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial–mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth via epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.

scholarly journals Tumour suppressor OTUD3 induces growth inhibition and apoptosis by directly deubiquitinating and stabilizing p53 in invasive breast carcinoma cells

2020 ◽  
Author(s):  
Qian Pu ◽  
Yan-Rong Lv ◽  
Ke Dong ◽  
Wen-Wen Geng ◽  
Hai-Dong Gao
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Protein Modification ◽  
Critical Role ◽  
Ectopic Expression ◽  
Chemotherapy Drugs ◽  
Amino Terminal

Abstract Background P53 pathway inactivation plays an important role in the process of breast cancer tumourigenesis. Post-translational protein modification abnormalities have been confirmed to be an important mechanism underlying the inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes are capable of deubiquitinating and stabilizing p53. Here, we report that OTUD3 is a deubiquitylase of p53 in breast carcinoma. Methods The correlation between the mRNA expression of OTUD3, TP53 and PTEN and the prognosis of BC was assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in breast carcinoma was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analysed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53. The interaction between OTUD3 and p53 in BC cells was verified by a co-immunoprecipitation assay and GST pulldown experiments. MTS proliferation detection, an apoptosis detection kit and colony formation asssy were used to investigate the functional effects of OTUD3 on breast cancer cells. Results OTUD3 downregulation is correlated with a poor prognosis in BC patients. OTUD3 expression is decreased in breast cancer tissues and independent of the histological grade.OTUD3 also inhibits cell proliferation and clone formation and increases the sensitivity of BC cells to apoptosis induced by chemotherapy drugs. A reduction in OTUD3 expression concomitant with decreased p53 abundance is correlated with human breast cancer progression. The ectopic expression of wild-type OTUD3, but not its catalytically inactive mutant, stabilizes and activates p53. Mechanistically, OTUD3 interacts directly with p53 through the amino-terminal OTU region. Finally, OTUD3 protects p53 from Mdm2-mediated ubiquitination and degradation, enabling the deubiquitination of p53 in BC cells. Conclusions In summary, we establish that OTUD3 is a potential therapeutic target for restoring p53 function in breast cancer cells and suggest that the OTUD3-p53 signalling axis plays a critical role in tumour suppression.

scholarly journals Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4390
Author(s):  
Liya Kondratyeva ◽  
Igor Chernov ◽  
Eugene Kopantzev ◽  
Dmitry Didych ◽  
Alexey Kuzmich ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Type I ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration

Intercellular interactions involving adhesion factors are key operators in cancer progression. In particular, these factors are responsible for facilitating cell migration and metastasis. Strengthening of adhesion between tumor cells and surrounding cells or extracellular matrix (ECM), may provide a way to inhibit tumor cell migration. Recently, we demonstrated that PDX1 ectopic expression results in the reduction of pancreatic cancer line PANC-1 cell motility in vitro and in vivo, and we now provide experimental data confirming the hypothesis that suppression of migration may be related to the effect of PDX1 on cell adhesion. Cell migration analyses demonstrated decreased motility of pancreatic Colo357 and PANC-1 cell lines expressing PDX1. We observed decreased expression levels of genes associated with promoting cell migration and increased expression of genes negatively affecting cell motility. Expression of the EMT regulator genes was only mildly induced in cells expressing PDX1 during the simulation of the epithelial-mesenchymal transition (EMT) by the addition of TGFβ1 to the medium. PDX1-expressing cancer cell lines showed increased cell adhesion to collagen type I, fibronectin, and poly-lysine. We conclude that ectopic expression of PDX1 reduces the migration potential of cancer cells, by increasing the adhesive properties of cells and reducing the sensitivity to TGFβ1-induced EMT.

scholarly journals Impairment of Membrane Lipid Homeostasis by Bichalcone Analog TSWU-BR4 Attenuates Function of GRP78 in Regulation of the Oxidative Balance and Invasion of Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 371
Author(s):  
Tsung-Lin Lee ◽  
Shyang-Guang Wang ◽  
Wen-Ling Chan ◽  
Ching-Hsiao Lee ◽  
Tian-Shung Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex Formation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lipid Raft ◽  
Cell Invasion ◽  
Membrane Trafficking ◽  
Ectopic Expression ◽  
Cancer Cell Invasion ◽  
Oxidative Balance

The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion.

scholarly journals Catalytically inactive human cathepsin D triggers fibroblast invasive growth

2005 ◽  
Vol 168 (3) ◽  
pp. 489-499 ◽  
Author(s):  
Valérie Laurent-Matha ◽  
Sharon Maruani-Herrmann ◽  
Christine Prébois ◽  
Mélanie Beaujouin ◽  
Murielle Glondu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Cathepsin D ◽  
Breast Cancer Cells ◽  
Mapk Pathway ◽  
Ectopic Expression ◽  
Three Dimensional ◽  
Fibroblast Cell ◽  
Invasive Growth ◽  
Invasive Capacity

The aspartyl-protease cathepsin D (cath-D) is overexpressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial–fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D–deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the ras–MAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity.

scholarly journals Role of integrin-linked kinase in regulating the protein stability of the MUC1-C oncoprotein in pancreatic cancer cells

Oncogenesis ◽  
2017 ◽  
Vol 6 (7) ◽  
pp. e359-e359 ◽  
Author(s):  
H-L Huang ◽  
H-Y Wu ◽  
P-C Chu ◽  
I-L Lai ◽  
P-H Huang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Stability ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Pancreatic Tumors ◽  
Alternative Mechanism ◽  
Pancreatic Cancer Cells ◽  
Integrin Linked Kinase

Abstract MUC1-C overexpression has been associated with the progression of pancreatic tumors by promoting the aggressive and metastatic phenotypes. As MUC1 is a STAT3 target gene, STAT3 plays a major role in regulating MUC1-C expression. In this study, we report an alternative mechanism by which integrin-linked kinase (ILK) post-transcriptionally modulates the expression of MUC1-C by maintaining its protein stability in pancreatic cancer cells. We found that ILK acts in concert with STAT3 to facilitate IL-6-mediated upregulation of MUC1-C; ILK depletion was equally effective as STAT3 depletion in abolishing IL-6-induced MUC1-C overexpression without disturbing the phosphorylation or cellular distribution of STAT3. Conversely, ectopic expression of constitutively active ILK increased MUC1-C expression, though this increase was not noted with kinase-dead ILK. This finding suggests the requirement of the kinase activity of ILK in regulating MUC1-C stability, which was confirmed by using the ILK kinase inhibitor T315. Furthermore, our data suggest the involvement of protein kinase C (PKC)δ in mediating the suppressive effect of ILK inhibition on MUC1-C repression. For example, co-immunoprecipitation analysis indicated that ILK depletion-mediated MUC1-C phosphorylation was accompanied by increased phosphorylation of PKCδ at the activation loop Thr-507 and increased binding of PKCδ to MUC1-C. Conversely, ILK overexpression resulted in decreased PKCδ phosphorylation. From a mechanistic perspective, the present finding, together with our recent report that ILK controls the expression of oncogenic KRAS through a regulatory loop, underscores the pivotal role of ILK in promoting pancreatic cancer progression.

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