HOTAIR promotes prostate cancer progression by mediating the interaction between Pol2S2 and CDK9 to maintain transcriptional elongation
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ABSTRACT:
PROVIDER: PRJNA913784 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22840500_1.fastq.gz | Fastqsanger.gz | |||
| SRR22840500_2.fastq.gz | Fastqsanger.gz | |||
| SRR22840501_1.fastq.gz | Fastqsanger.gz | |||
| SRR22840501_2.fastq.gz | Fastqsanger.gz | |||
| SRR22840502_1.fastq.gz | Fastqsanger.gz |
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Project description:Previous research has predominantly focused on the regulatory role of lncRNA HOTAIR in gene silencing through its interaction with the Polycomb repressive complex 2 (PRC2). Here, our study uncovers a novel regulatory mechanism of HOTAIR, which facilitates prostate cancer (PCa) progression by sustaining transcription elongation. Using ChIRP-seq, RNA-seq, and ChIP-seq, we successfully mapped the binding sites of HOTAIR across the genome and determined their interplay with the epigenetic landscape. We discovered that the co-localization of HOTAIR with the androgen receptor (AR) can activate gene transcription. In the context of AR binding, we discovered that HOTAIR maintains transcription elongation by facilitating the formation of the CDK9/Pol2S2 complex. We revealed a unique capacity of HOTAIR to promote transcriptional activation on gene promoters/bodies with low H3K27me3 enrichment, a function contrasting to its established PRC2-related transcriptional inhibitory roles in regions with high H3K27me3 signal. Finally, we identified two direct target genes of HOTAIR (MMP14 and TNFAIP2), which contribute to the progression of PCa. Collectively, our research sheds new light on HOTAIR's role in transcriptional regulation, offering potential therapeutic strategies and expand our understanding of HOTAIR's roles in PCa progression. In this study, we used ChIRP-seq to identify HOTAIR binding sites on genome-wide of PCa cells. Then, for purpose of associating chromatin location of HOTAIR to epigenetic landscape, we profiled repressed histone mark (H3K27me3) and active histone mark (H3K27ac). Finally, we integrated data of ChIRP-seq, RNA-seq and ChIP-seq for a complete analysis. We identified that HOTAIR can co-locate with AR to enhance transcription elongation on low H3K27m3 enrichment gene body/promoter, which differs from the function of HOTAIR on high H3K27me3 enrichment region.
2024-03-26 | GSE221263 | GEO
Project description:Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy. Comparision of MDA-MB-231 Breast Cancer Cells expressing vector or HOTAIR. Each cell line was subjected to ChIP-chip with anti-H3K27, SUZ12, and EZH2 and interrogated on whole genome promoter arrays
2010-03-16 | E-GEOD-20737 | biostudies-arrayexpress
Project description:The long-non-coding HOX transcript antisense intergenic RNA (HOTAIR) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by HOTAIR in early-stage breast cancer progression. We determined that HOTAIR induces premalignant phenotypic changes by increasing cell proliferation, migration, invasion and in vivo growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by HOTAIR which include bioprocesses related to cell migration, epithelial to mesenchymal transition, extracellular matrix remodeling and activation of HIF1A, AP1 and FGFR signaling pathways among others. Similar pathways were identified as activated in primary invasive breast carcinomas with HOTAIR over-expression. We conclude that HOTAIR over-expression behaves as a positive regulator of cell growth and migration both in normal and DCIS breast cells involved with early-stage breast cancer progression.
2021-11-01 | GSE183058 | GEO
Project description:Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
2010-03-16 | GSE20737 | GEO
Project description:LNCaP prostate cancer cells were infected by lentivirus expressing either ctrl or HOTAIR. The cells were cultured either in hormone-deprived condition (Ethl) or in the presence of androgen( R1881).
2015-10-01 | GSE61269 | GEO
Project description:Long noncoding RNA HOTAIR (HOX antisense intergenic RNA) is an important regulator of breast cancer metastasis. Studies showed that HOTAIR reprograms chromatin state through interacting with Polycomb Repressive Complex 2 (PRC2) to promote breast cancer metastasis. However, it is unclear if there exist other HOTAIR-binding factors which participate in promoting breast cancer metastasis. In the current study, we utilized mass spectrometry (ChIRP-MS) to comprehensively identify RNA-binding proteins (RBPs) associated with HOTAIR. We also performed a high-throughput CRISPR screen to investigate HOTAIR-interacting proteins involved in cell metastasis. We found that many m6A-reader proteins were involved in this progress, including YTHDF3, which is a newly identified HOTAIR partner. We further demonstrated that HOTAIR and YTHDF3 co-regulated the expression of several metastasis-associated genes by modifying their chromatin accessibility in breast cancer cells. Altogether, our work detailed the functional interactome of HOTAIR involved in promoting breast cancer cell metastasis, and suggested a mechanism whereby HOTAIR regulates chromatin state in cooperation with the m6A-reader YTHDF3.
2025-10-10 | GSE215289 | GEO
Project description:Long noncoding RNA HOTAIR (HOX antisense intergenic RNA) is an important regulator of breast cancer metastasis. Studies showed that HOTAIR reprograms chromatin state through interacting with Polycomb Repressive Complex 2 (PRC2) to promote breast cancer metastasis. However, it is unclear if there exist other HOTAIR-binding factors which participate in promoting breast cancer metastasis. In the current study, we utilized mass spectrometry (ChIRP-MS) to comprehensively identify RNA-binding proteins (RBPs) associated with HOTAIR. We also performed a high-throughput CRISPR screen to investigate HOTAIR-interacting proteins involved in cell metastasis. We found that many m6A-reader proteins were involved in this progress, including YTHDF3, which is a newly identified HOTAIR partner. We further demonstrated that HOTAIR and YTHDF3 co-regulated the expression of several metastasis-associated genes by modifying their chromatin accessibility in breast cancer cells. Altogether, our work detailed the functional interactome of HOTAIR involved in promoting breast cancer cell metastasis, and suggested a mechanism whereby HOTAIR regulates chromatin state in cooperation with the m6A-reader YTHDF3.
2025-10-10 | GSE215284 | GEO
Project description:HOTAIR is a 2.2 kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background (iHOT-PyMT mice) to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We isolated breast cancer cells from the primary tumors of iHOT-PyMT mice (named iHOT+ cells) and performed RNA-seq and ATAC-seq of iHOT+ cells treated with 3 conditions: Dox+, Dox- and DoxWD. We showed that HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted epithelial to mesenchymal transition. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program.
2023-01-10 | GSE201582 | GEO
Project description:The human long noncoding RNA (lncRNA) HOTAIR acts in trans to recruit the Polycomb Repressive Complex 2 (PRC2) to the HOXD gene cluster and promote gene silencing during development. In breast cancers, overexpression of HOTAIR increases metastatic potential via the repression of many additional genes. It has remained unclear what factors determine HOTAIR-dependent PRC2 activity at specific genomic loci, particularly when high levels of HOTAIR result in aberrant gene silencing. To identify additional proteins that contribute to the specific action of HOTAIR, we performed a quantitative proteomic analysis of the HOTAIR interactome. We found that the most specific interaction was between HOTAIR and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, a member of a family of proteins involved in nascent mRNA processing and RNA matchmaking. Our data suggest that A2/B1 are key contributors to HOTAIR-mediated chromatin regulation in breast cancer cells: A2/B1 knockdown reduces HOTAIR-dependent breast cancer cell invasion and decreases PRC2 activity at the majority of HOTAIR-dependent loci. We found that the B1 isoform, which differs from A2 by 12 additional amino acids, binds with highest specificity to HOTAIR. B1 also binds chromatin and associates preferentially with RNA transcripts of HOTAIR gene targets. We furthermore demonstrate a direct RNA-RNA interaction between HOTAIR and a target transcript that is enhanced by B1 binding. Together, these results suggest a model in which B1 matches HOTAIR with transcripts of target genes on chromatin, leading to repression by PRC2.
2016-05-09 | GSE73702 | GEO
Project description:Epithelial-to-mesenchymal transitions (EMT) underlie a loss of epithelial traits by normal cells during development and neoplastic cells during cancer metastasis. The long noncoding RNA HOTAIR triggers EMT, in part by serving as a scaffold for Polycomb Repressive Complex 2 (PRC2) and thus promoting repressive histone H3 Lys27 methylation. In addition to PRC2, HOTAIR interacts with the Lsd1 lysine demethylase, an epigenetic regulator of cell fate during development and differentiation. Here, we showed that HOTAIR requires the Lsd1-interacting domain, but not the PRC2-interacting domain, to promote migration of epithelial cells. Our results suggest that the HOTAIR-Lsd1 asociation redistributes Lsd1 on chromatin and hence reprograms the epithelial transcriptome.
2021-04-22 | GSE162937 | GEO