H2A.Z acetylation by lincZNF337-AS1 via KAT5 implicated in the transcriptional misregulation in cancer signaling pathway in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Yuan Y
PROVIDER: S-EPMC8197763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:H2A.Z is an essential histone variant that has been implicated to have multiple chromosomal functions. To understand how H2A.Z participates in such diverse activities, we sought to identify downstream effector proteins that are recruited to chromatin via H2A.Z. For this purpose, we developed a nucleosome purification method to isolate H2A.Z-containing nucleosomes from human cells and used mass spectrometry to identify the co-purified nuclear proteins. Through stringent filtering, we identified the top 21 candidates, many of which have conserved structural motifs that bind post-translationally modified histones. We further validated the biological significance of one such candidate, Brd2, which is a double-bromodomain-containing protein known to function in transcriptional activation. We found that Brd2's preference for H2A.Z nucleosomes is mediated through a combination of hyperacetylated H4 on these nucleosomes, as well as additional features on H2A.Z itself. In addition, comparison of nucleosomes containing either H2A.Z-1 or H2A.Z-2 isoforms showed that significantly more Brd2 co-purifies with the former, suggesting these two isoforms engage different downstream effector proteins. Consistent with these biochemical analyses, we found that Brd2 is recruited to AR-regulated genes in an H2A.Z-dependent manner and that chemical inhibition of Brd2 recruitment greatly inhibits AR-regulated gene expression. Taken together, we propose that Brd2 is a key downstream mediator that links H2A.Z and transcriptional activation of AR-regulated genes. Moreover, this study validates the approach of using proteomics to identify nucleosome-interacting proteins in order to elucidate downstream mechanistic functions associated with the histone variant H2A.Z.
| S-EPMC3493454 | biostudies-literature
Project description:PurposeH2A.Z is an oncogenic histone variant that is overexpressed in cancers. Two isoforms of H2A.Z, H2AFZ and H2AFV, are identical except for a three-amino acid difference. However, their isoform-specific functions remain unclear in cancer development. Thereby, this study aimed to investigate whether the two isoforms play distinct functions in hepatocarcinogenesis.Materials and MethodsExpressions of H2A.Z isoforms in 116 paired hepatocellular cancerous and para-cancerous tissues were detected by employing qPCR. GEO and TCGA databases were used to probe expressions and prognostic value of the two H2A.Z isoforms. A comprehensive meta-analysis was conducted. Furthermore, co-expressed analysis of H2AFZ and H2AFV ?was performed by using cBioPortal database. H2A.Z binding genes from Chip-seq were intersected with H2A.Z isoforms co-expressed genes to perform functional annotations. Cell proliferation experiments from H2AFZ knockout HepG2 and BEL-7402 cells were implemented. Finally, RNA-seq was applied to analyse alternative splicing in H2AFZ knockout and wild-type cells.ResultsH2AFZ and H2AFV were both significantly upregulated (P < 0.01) in hepatocellular carcinoma and related to poor prognosis (P < 0.01). The two H2A.Z isoforms played vital roles in cell proliferation. It is also predicted that unique functions of H2AFV contain spindle midzone and microtubule, while H2AFZ is especially associated with RNA export and spliceosome. Further, devoid H2AFZ may restrain liver cancer cell proliferation and cause many alternative splicing events.ConclusionBoth H2A.Z isoforms play vital and distinct roles in the occurrence and progression of liver cancer, which may pave a way for novel therapeutic applications for cancers in the future.
| S-EPMC7244249 | biostudies-literature
Project description:Transcription factor SOX4 has been implicated in skeletal myoblast differentiation through the regulation of Cald1 gene expression; however, the detailed molecular mechanism underlying this process is largely unknown. Here, we demonstrate that SOX4 acetylation at lysine 95 by KAT5 (also known as Tip60) is essential for Cald1 promoter activity at the onset of C2C12 myoblast differentiation. KAT5 chromodomain was found to facilitate SOX4 recruitment to the Cald1 promoter, which is involved in chromatin remodeling at the promoter. Chromatin occupancy analysis of SOX4, KAT5, and HDAC1 indicated that the expression of putative SOX4 target genes during C2C12 myoblast differentiation is specifically regulated by the molecular switching of the co-activator KAT5 and the co-repressor HDAC1 on SOX4 transcriptional activation.
| S-EPMC4558493 | biostudies-literature
Project description:Background:It has reported that long non-coding RNAs (lncRNAs) exerted regulatory functions by targeting specific genes through a competing endogenous RNA (ceRNA) pathway. LncRNA OIP5-AS1 has been identified as a tumor-enhancer in several tumor types. Nonetheless, its molecular mechanism in HCC remains to be masked. Aim of the study:This study was aimed at exploring whether and how OIP5-AS1 exert functions in HCC. Methods:qRT-PCR and western blot were employed for detecting gene expression. CCK-8, colony formation and EdU assays were implemented to evaluate the proliferative ability of HCC cells. Caspase-3 activity and flow cytometry analyses were implemented to determine cell apoptosis and cell cycle distribution. RNA pull down, ChIP, RIP and luciferase reporter assays explored the interplays between molecules. Results:YY1 was upregulated in HCC cells, and silenced YY1 restrained HCC cell proliferation in vitro and hampered tumor growth in vivo. Later, we discovered that miR-300 could regulate WNT pathway via targeting YY1. Furthermore, OIP5-AS1 was identified as the sponge of miR-300 and promoted cell growth in HCC. Importantly, YY1 transcriptionally activate OIP5-AS1 in turn. Rescue experiments indicated that miR-300 inhibition or YY1 overexpression abrogated the inhibitive effect of OIP5-AS1 silencing on the malignant growth of HCC cells. Conclusions:OIP5-AS1/miR-300/YY1 feedback loop facilitates cell growth in HCC by activating WNT pathway.
| S-EPMC7487829 | biostudies-literature
Project description:Background:Hepatocellular carcinoma (HCC) is a very belligerent primary liver tumor with high metastatic potential. Aberrant expression of lncRNAs drives tumorous invasion and metastasis. Whether lncRNAs engage mechanisms of liver cancer metastasis remains largely unexplored. Patients and Methods:We collected HCC tissues from the tumors and their adjacent normal samples in the Chinese population and analyzed the levels of lncRNAs by microarray analysis. The gain- and loss-of-function analysis demonstrated that PCBP1-AS1 accelerated tumorous growth and metastasis in vivo and in vitro. Moreover, we used RNA-pulldown assay to show that PCBP1-AS1 physically interacted with polyC-RNA-binding protein 1 (PCBP1); meanwhile, PCBP1-AS1 was indeed detected in RIP with the PCBP1 antibody. Mechanistically, we first explored the relationship between PCBP1-AS1 and PCBP1 in HCC cell lines. Results:Here we show that PCBP1-AS1, identified by microarray analysis on pre- and post-operative HCC plasma specimens, was highly expressed in human HCC, clinically verified as a prometastatic factor and markedly associated with poor prognosis in patients with hepatocellular carcinoma. PCBP1-AS1 was negatively related with PCBP1 at the messenger RNA and protein expression levels. PCBP1-AS1 triggered PRL-3 and AKT in HCC tumor cells. Additionally, the double knockout of PCBP1 and PCBP1-AS1 abolished the PCBP1-AS1-induced PRL-3-AKT signalling pathway activation. Conclusion:The upregulation of PCBP1-AS1 enhances proliferation and metastasis in HCC, thus regulating the PCBP1-PRL-3-AKT signalling pathway.
| S-EPMC7352448 | biostudies-literature
Project description:IGF2BP1 overexpression promotes hepatocellular carcinoma (HCC) progression. Long non-coding RNA LIN28B-AS1 directly binds to IGF2BP1. In the present study, LIN28B-AS1 and IGF2BP1 expression and their potential functions in HCC cells were tested. Genetic strategies were applied to interfere their expression, and cell survival, proliferation and apoptosis were analyzed. We show that LIN28B-AS1 is expressed in established/primary human HCC cells and HCC tissues. RNA-immunoprecipitation (RIP) and RNA pull-down results confirmed that LIN28B-AS1 directly associated with IGF2BP1 protein in HCC cells. LIN28B-AS1 silencing (by targeted siRNAs) or knockout (KO, by CRISPR-Cas9 method) depleted IGF2BP1-dependent mRNAs (IGF2, Gli1, and Myc), inhibiting HCC cell growth, proliferation, migration, and invasion. Conversely, ectopic overexpression of LIN28B-AS1 upregulated IGF2BP1-dependent mRNAs and promoted HCC cell progression in vitro. Importantly, ectopic IGF2BP1 overexpression failed to rescue LIN28B-AS1-KO HepG2 cells. LIN28B-AS1 siRNA and overexpression were ineffective in IGF2BP1-KO HepG2 cells. In vivo, LIN28B-AS1 KO-HepG2 xenograft tumors grew significantly slower than the control tumors in the nude mice. Taken together, we conclude that LIN28B-AS1 associates with IGF2BP1 to promote human HCC cell progression in vitro and in vivo.
| S-EPMC7486890 | biostudies-literature
Project description:BackgroundGlutaminolysis is a critical metabolic process that promotes cancer cell proliferation, including hepatocellular carcinoma (HCC). Delineating the molecular control of glutaminolysis could identify novel targets to ameliorate this oncogenic metabolic pathway. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a regulator of mitochondrial protein acetylation, in modulating the acetylation and activity of glutaminase to regulate HCC development.MethodsCell proliferation was determined by MTT, 2D and soft agar clone formation assays and orthotopic tumour assays in nude mice. GLS1/2 acetylation and activities were measured in cells and tumours to analyse the correlation with GCN5L1 expression and mTORC1 activation.ResultsHepatic GCN5L1 ablation in mice markedly increased diethylnitrosamine (DEN)-induced HCC, and conversely, the transduction of mitochondrial-restricted GCN5L1 protected wild-type mice against HCC progression in response to DEN and carbon tetrachloride (CCl4 ) exposure. GCN5L1-depleted HepG2 hepatocytes enhanced tumour growth in athymic nude mice. Mechanistically, GCN5L1 depletion promoted cell proliferation through mTORC1 activation. Interestingly, liver-enriched glutaminase 2 (GLS2) appears to play a greater role than ubiquitous and canonical tumour-enriched glutaminase 1 (GLS1) in promoting murine HCC. Concurrently, GCN5L1 promotes acetylation and inactivation of both isoforms and increases enzyme oligomerisation. In human HCC tumours compared to adjacent tissue, there were variable levels of mTORC1 activation, GCN5L1 levels and glutaminase activity. Interestingly, the levels of GCN5L1 inversely correlated with mTORC1 activity and glutaminase activity in these tumours.ConclusionsOur study identified that glutaminase activity, rather than GLS1 or GLS2 expression, is the key factor in HCC development that activates mTORC1 and promotes HCC. In the Kaplan-Meier analysis of liver cancer, we found that HCC patients with high GCN5L1 expression survived longer than those with low GCN5L1 expression. Collectively, GCN5L1 functions as a tumour regulator by modulating glutaminase acetylation and activity in the development of HCC.
| S-EPMC9091986 | biostudies-literature
Project description:H2A.Z is a histone H2A variant conserved from yeast to humans, and is found at 63% of promoters in Saccharomyces cerevisiae. This pattern of localization suggests that H2A.Z is somehow important for gene expression or regulation. H2A.Z can be acetylated at up to four lysine residues on its amino-terminal tail, and acetylated-H2A.Z is enriched in chromatin containing promoters of active genes. We investigated whether H2A.Z's role in GAL1 gene regulation and gene expression depends on H2A.Z acetylation. Our findings suggested that H2A.Z functioned both in gene regulation and in gene expression and that only its role in gene regulation depended upon its acetylation. Our findings provided an alternate explanation for results that were previously interpreted as evidence that H2A.Z plays a role in GAL1 transcriptional memory. Additionally, our findings provided new insights into the phenotypes of htz1Delta mutants: in the absence of H2A.Z, the SWR1 complex, which deposits H2A.Z into chromatin, was deleterious to the cell, and many of the phenotypes of cells lacking H2A.Z were due to the SWR1 complex's activity rather than to the absence of H2A.Z per se. These results highlight the need to reevaluate all studies on the phenotypes of cells lacking H2A.Z.
| S-EPMC2889906 | biostudies-literature
Project description:Growing evidence has revealed that hypoxia is involved in multiple stages of cancer development. However, there are limited reports on the effects of long noncoding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) progression under hypoxia. The main purposes of this study were to analyze the effect of the novel lncRNA DACT3-AS1 on metastasis in HCC and to elucidate the related molecular mechanism. Bioinformatics tools were employed. RT-qPCR or western blot assays were conducted to detect RNA or protein expression. Clinical samples and in vivo assays were utilized to reveal the role of DACT3-AS1 in HCC. Other mechanism and functional analyses were specifically designed and performed as well. Based on the collected data, this study revealed that HIF-1α transcriptionally activates DACT3-AS1 expression under hypoxia. DACT3-AS1 was verified to promote metastasis in HCC. Mechanistically, DACT3-AS1 promotes the interaction between HDAC2 and FOXA3 to stimulate FOXA3 deacetylation, which consequently downregulates the FOXA3 protein. Furthermore, FOXA3 serves as a transcription factor that can bind to the PKM2 promoter region, thus hindering PKM2 expression. To summarize, this study uncovered that HIF-1α-induced DACT3-AS1 promotes metastasis in HCC and can upregulate PKM2 via the HDAC2/FOXA3 pathway in HCC cells.
| S-EPMC9256752 | biostudies-literature
Project description:Hepatocellular Carcinoma (HCC) is one of the most fatal cancers, whose incidence and death rates are still rising. Here, we report the identification of long non-coding RNAs (IncRNAs) that associated with HCC progression and metabolism based on the systematically analysis of large scale RNA-seq data from HCC patients. We identified seven lncRNAs with high confidence which were highly related with prognostic of HCC. Of note, three of them had quite different expression patterns between the control samples and the patients, and their critical roles in cancer progression were validated. We proposed that DDX11-AS1 play important role during HCC oncogenesis and may serve as potential therapy target for HCC.
| S-EPMC5546473 | biostudies-literature