Aberrant Expression Patterns of Histone H3 mRNA, p53, Cyclin D1, and Cyclin B1 in Oral Neoplastic Epithelial Lesions

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

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Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia

Annals of the National Academy of Medical Sciences (India) ◽

10.1055/s-0041-1726151 ◽

2021 ◽

Author(s):

Mohit Arora ◽

Garima Pandey ◽

Shyam S. Chauhan

Keyword(s):

Antigen Processing ◽

Hematological Malignancies ◽

Expression Patterns ◽

Aberrant Expression ◽

Hematopoietic Stem ◽

Cysteine Cathepsins ◽

Expression Activity ◽

Available Information ◽

Antigen Processing And Presentation ◽

Selection Of

AbstractCysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.

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Expression Patterns and Post-translational Modifications Associated with Mammalian Histone H3 Variants

Journal of Biological Chemistry ◽

10.1074/jbc.m509266200 ◽

2005 ◽

Vol 281 (1) ◽

pp. 559-568 ◽

Cited By ~ 213

Author(s):

Sandra B. Hake ◽

Benjamin A. Garcia ◽

Elizabeth M. Duncan ◽

Monika Kauer ◽

Graham Dellaire ◽

...

Keyword(s):

Expression Patterns ◽

Histone H3 ◽

Post Translational Modifications

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S-Phase Progression Mediates Activation of a Silenced Gene in Synthetic Nuclei

Molecular and Cellular Biology ◽

10.1128/mcb.20.11.4169-4180.2000 ◽

2000 ◽

Vol 20 (11) ◽

pp. 4169-4180 ◽

Cited By ~ 5

Author(s):

Alison J. Crowe ◽

Julie L. Piechan ◽

Ling Sang ◽

Michelle C. Barton

Keyword(s):

Dna Replication ◽

Developmental Stage ◽

Expression Patterns ◽

Marker Gene ◽

Nuclear Extract ◽

S Phase ◽

Developmental Expression ◽

Aberrant Expression ◽

Transcription Repressors

ABSTRACT Aberrant expression of developmentally silenced genes, characteristic of tumor cells and regenerating tissue, is highly correlated with increased cell proliferation. By modeling this process in vitro in synthetic nuclei, we find that DNA replication leads to deregulation of established developmental expression patterns. Chromatin assembly in the presence of adult mouse liver nuclear extract mediates developmental stage-specific silencing of the tumor marker gene alpha-fetoprotein (AFP). Replication of silenced AFP chromatin in synthetic nuclei depletes sequence-specific transcription repressors, thereby disrupting developmentally regulated repression. Hepatoma-derived factors can target partial derepression of AFP, but full transcription activation requires DNA replication. Thus, unscheduled entry into S phase directly mediates activation of a developmentally silenced gene by (i) depleting developmental stage-specific transcription repressors and (ii) facilitating binding of transactivators.

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IMP3 Protein Overexpression Is Linked to Unfavorable Outcome in Laryngeal Squamous Cell Carcinoma

Cancers ◽

10.3390/cancers13174306 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4306

Author(s):

Diana Maržić ◽

Blažen Marijić ◽

Tamara Braut ◽

Stefan Janik ◽

Manuela Avirović ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Protein Expression ◽

Cell Carcinoma ◽

Cyclin D1 ◽

Squamous Cell ◽

Expression Patterns ◽

Low Grade ◽

Benign Lesions ◽

Ki 67 ◽

Neck Node

Background: The aim of this study was to (i) determine IMP3 protein expression in benign and malignant laryngeal lesions, (ii) compare its expression to Ki-67, p53, cyclin D1, and (iii) finally, to examine the prognostic power of IMP3 in squamous cell carcinomas of the larynx (LSSC). Methods: IMP3 protein expression was evaluated in 145 patients, including 62 LSCC, 45 dysplasia (25 with low and 20 with high-grade dysplasia), and 38 benign lesions (vocal cord polyps and nodules). Results: IMP3 was significantly higher expressed in LSCC compared to dysplasia and benign lesions (p < 0.001; p < 0.001, respectively). Similarly, higher expression patterns were observed for Ki-67 and p53, whereas cyclin D1 was equally distributed in all three lesions. IMP3 (p = 0.04) and Ki-67 (p = 0.02) expressions were significantly linked to neck node positivity, and IMP3 overexpression to worse disease-specific survival (p = 0.027). Conclusion: Since IMP3 showed significantly higher expression in laryngeal carcinomas, but not in high- or low-grade dysplasia, it serves as a useful marker to differentiate between invasive and noninvasive lesions. Higher IMP3 expression represented a significantly worse prognosticator for clinical outcomes of patients with squamous cell carcinoma of the larynx.

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Global Histone H3 Lysine 4 Trimethylation (H3K4me3) Landscape Changes in Response to TGFβ

Epigenetics Insights ◽

10.1177/25168657211051755 ◽

2021 ◽

Vol 14 ◽

pp. 251686572110517

Author(s):

Ankit Naik ◽

Nidhi Dalpatraj ◽

Noopur Thakur

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Expression Patterns ◽

Histone H3 ◽

Epigenetic Mechanism ◽

Stable Gene ◽

Regulation Of Transcription ◽

Functional Categories ◽

Positive Regulation ◽

Histone H4 Acetylation

TGFβ expression acts as a biomarker of poor prognosis in prostate cancer. It plays a dual functional role in prostate cancer. In the early stages of the tumor, it acts as a tumor suppressor while at the later stages of tumor development, it promotes metastasis. The molecular mechanisms of action of TGFβ are largely understood through the canonical and non-canonical signal transduction pathways. Our understanding of the mechanisms that establish transient TGFβ stimulation into stable gene expression patterns remains incomplete. Epigenetic marks like histone H3 modifications are directly linked with gene expression and they play an important role in tumorigenesis. In this report, we performed chromatin immunoprecipitation-sequencing (ChIP-Seq) to identify the genome-wide regions that undergo changes in histone H3 Lysine 4 trimethylation (H3K4me3) occupancy in response to TGFβ stimulation. We also show that TGFβ stimulation can induce acute epigenetic changes through the modulation of H3K4me3 signals at genes belonging to special functional categories in prostate cancer. TGFβ induces the H3K4me3 on its own ligands like TGFβ, GDF1, INHBB, GDF3, GDF6, BMP5 suggesting a positive feedback loop. The majority of genes were found to be involved in the positive regulation of transcription from the RNA polymerase II promoter in response to TGFβ. Other functional categories were intracellular protein transport, brain development, EMT, angiogenesis, antigen processing, antigen presentation via MHC class II, lipid transport, embryo development, histone H4 acetylation, positive regulation of cell cycle arrest, and genes involved in mitotic G2 DNA damage checkpoints. Our results link TGFβ stimulation to acute changes in gene expression through an epigenetic mechanism. These findings have broader implications on epigenetic bases of acute gene expression changes caused by growth factor stimulation.

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Abstract P104: Reactivation of Embryonic Gene Program due to CUG Repeat RNA Expression in Myotonic Dystrophy

Circulation Research ◽

10.1161/res.109.suppl_1.ap104 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Auinash Kalsotra ◽

Ravi Singh ◽

Chad Creighton ◽

Thomas Cooper

Keyword(s):

Gene Expression ◽

Myotonic Dystrophy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Expression Patterns ◽

Causative Mutation ◽

Inherited Disease ◽

Aberrant Expression ◽

Organ Systems ◽

General Response

Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac involvement, which is characterized by conduction defects and arrhythmias, is the second leading cause of death in DM1 patients. The causative mutation is a CTG expansion in the 3' untranslated region of DMPK gene resulting in aberrant expression of CUG repeat RNA that accumulates into nuclear foci and causes misregulation in alternative splicing. Here we show that heart-specific and inducible expression of CUG repeat RNA in a DM1 mouse model results in global reactivation of embryonic gene expression program in adult heart that is distinct from a general hypertrophic stress response. Using q-PCR TaqMan arrays, we identified 54 miRNAs that were differentially expressed in DM1 mouse hearts one week following induction of CUG repeat RNA. Interestingly, 83% (45/54) of them exhibited a developmental shift in expression towards the embryonic pattern. Because over 90% (41/45) of them were down regulated within 72 hr after induction of repeat RNA and only 2/22 examined decreased in two unrelated mouse models of heart disease, we conclude their reduced expression is specific to DM1 and not simply a general response to cardiac injury. Microarray studies revealed a developmental switch not only in the miRNA expression patterns but also a pervasive shift in mRNA steady state levels of a number of genes to embryonic stage. Intriguingly, we found that loss of MBNL1 or gain of CELF1 activity, two major RNA binding proteins disrupted in DM1, are not driving the miRNA misregulation since their expression is indistinguishable between wild type, MBNL1 knock out and CELF1 over expressing mice. Moreover, comparable decrease in ten out of ten primary miRNA transcripts examined suggests loss of expression is not due to a processing defect. Instead, we discovered that adult-to-embryonic shift in expression of select micro- and messenger RNAs in DM1 heart occurs due to specific inactivation of a Mef2 transcriptional program. We are currently determining causal contributions of this Mef2-miRNA circuitry in the developmental reprogramming of gene expression in DM1 as well as its direct role in cardiac manifestations of this disease.

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Genome-wide expression profiling in colorectal cancer focusing on lncRNAs in the adenoma-carcinoma transition

BMC Cancer ◽

10.1186/s12885-019-6180-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 8

Author(s):

Alexandra Kalmár ◽

Zsófia Brigitta Nagy ◽

Orsolya Galamb ◽

István Csabai ◽

András Bodor ◽

...

Keyword(s):

Colorectal Cancer ◽

Differential Expression ◽

Colorectal Adenoma ◽

Expression Profiles ◽

Expression Patterns ◽

Aberrant Expression ◽

Array Data ◽

Lncrna Expression ◽

Qrt Pcr ◽

Mrna Targets

Abstract Background Long non-coding RNAs (lncRNAs) play a fundamental role in colorectal cancer (CRC) development, however, lncRNA expression profiles in CRC and its precancerous stages remain to be explored. We aimed to study whole genomic lncRNA expression patterns in colorectal adenoma–carcinoma transition and to analyze the underlying functional interactions of aberrantly expressed lncRNAs. Methods LncRNA expression levels of colonic biopsy samples (20 CRCs, 20 adenomas (Ad), 20 healthy controls (N)) were analyzed with Human Transcriptome Array (HTA) 2.0. Expression of a subset of candidates was verified by qRT-PCR and in situ hybridization (ISH) analyses. Furthermore, in silico validation was performed on an independent HTA 2.0, on HGU133Plus 2.0 array data and on the TCGA COAD dataset. MiRNA targets of lncRNAs were predicted with miRCODE and lncBase v2 algorithms and miRNA expression was analyzed on miRNA3.0 Array data. MiRNA-mRNA target prediction was performed using miRWALK and c-Met protein levels were analyzed by immunohistochemistry. Comprehensive lncRNA-mRNA-miRNA co-expression pattern analysis was also performed. Results Based on our HTA results, a subset of literature-based CRC-associated lncRNAs showed remarkable expression changes already in precancerous colonic lesions. In both Ad vs. normal and CRC vs. normal comparisons 16 lncRNAs, including downregulated LINC02023, MEG8, AC092834.1, and upregulated CCAT1, CASC19 were identified showing differential expression during early carcinogenesis that persisted until CRC formation (FDR-adjusted p < 0.05). The intersection of CRC vs. N and CRC vs. Ad comparisons defines lncRNAs characteristic of malignancy in colonic tumors, where significant downregulation of LINC01752 and overexpression of UCA1 and PCAT1 were found. Two candidates with the greatest increase in expression in the adenoma-carcinoma transition were further confirmed by qRT-PCR (UCA1, CCAT1) and by ISH (UCA1). In line with aberrant expression of certain lncRNAs in tumors, the expression of miRNA and mRNA targets showed systematic alterations. For example, UCA1 upregulation in CRC samples occurred in parallel with hsa-miR-1 downregulation, accompanied by c-Met target mRNA overexpression (p < 0.05). Conclusion The defined lncRNA sets may have a regulatory role in the colorectal adenoma-carcinoma transition. A subset of CRC-associated lncRNAs showed significantly differential expression in precancerous samples, raising the possibility of developing adenoma-specific markers for early detection of colonic lesions.

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