Prostate cancer cell lines modulated with OC2 Protein or 3' UTR
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ABSTRACT:
PROVIDER: PRJNA983863 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor ONECUT2 (OC2) is a master transcriptional regulator operating in metastatic castrate-resistant prostate cancer (mCRPC) that suppresses AR activity and promotes neural differentiation and tumor cell survival. OC2 mRNA possesses an unusually long (14,575 nt), evolutionarily conserved 3’-untranslated region (3’-UTR) with many microRNA binding sites, including up to 26 miR-9 sites. This is notable because miR-9 targets many of the same genes regulated by the OC2 protein. Paradoxically, OC2 expression is high in tissues with high miR-9 expression. The length and complex secondary structure of the OC2 mRNA suggests it is a potent master competing endogenous RNA (ceRNA) capable of sequestering miRNAs. Here we describe a novel role for the OC2 3’-UTR in lethal prostate cancer consistent with a function as a ceRNA. A plausible ceRNA network in OC2-driven tumors was constructed computationally then confirmed in prostate cancer cell lines. Genes regulated by the OC2 3’-UTR exhibited high overlap (up to 45%) with genes driven by overexpression of the OC2 protein in the absence of the 3’-UTR, indicating a cooperative functional relationship between the OC2 protein and its 3’-UTR. These overlapping networks suggest an evolutionarily conserved mechanism to reinforce OC2 transcription by protection of OC2-regulated mRNAs from miRNA suppression. Both the protein and the 3’ UTR showed increased Polycomb Repressive Complex activity. Expression of OC2 3’-UTR mRNA alone (without protein) dramatically increased metastatic potential by in vitro assays. Additionally, OC2 3’-UTR increased expression of Aldo-Keto Reductase and UDP-glucuronyl transferase family genes responsible for altering the androgen synthesis pathway. ONECUT2 represents the first described dual-modality transcript that operates as both a key transcription factor driving castration resistant prostate cancer but also as a master ceRNA that promotes and protects the same transcriptional network
2023-06-19 | GSE235003 | GEO
Project description:We profiled the proteomics of prostate cancer (PCa) cell lines.
2024-12-06 | PXD058635 |
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE217530 | GEO
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE200303 | GEO
Project description:Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer with a high mortality rate due to a current lack of treatment options. While much is already known about how mutations in protein-coding sequences across the genome affect prostate cancer, somatic mutations occurring in the 3’ untranslated regions (3’UTRs) of genes are largely unstudied. The 3’UTR is a genomic region that controls post-transcriptional gene expression through its recruitment of trans-acting factors such as RNA-binding proteins (RBPs) and microRNAs (miRNAs), which themselves are known to be oncogenes and tumor suppressors in many cases. To better understand the role of 3’UTR mutations across prostate cancer, we have created a database of 3’UTR somatic mutations in 185 patients with mCRPC, discovering 14,497 single-nucleotide mutations throughout the 3’UTRome. In order to functionally assay these variants, we have developed a novel pair of massively parallel reporter assays (MPRA) able to determine the effect of thousands of patient somatic mutations on post-transcriptional gene expression. In this two-pronged approach, we are able to measure whether each of 6,892 mutations found in recurrently mutated 3’UTRs affect mRNA stability, steady-state transcript level, and translation efficiency. This deep functional assessment of thousands of 3’UTR mutations allows us to uncover patterns in mutation functionality, including their association with RNA motifs and sequence conservation. Investigation into how the resultant gene expression changes from 3’UTR mutations affect prostate cancer pathogenesis, such as cancer growth or response to treatment, is also underway. This work represents an unprecedented view of the extent to which disease-relevant 3’UTR mutations affect mRNA stability, translation efficiency, and cancer phenotypes, expanding the boundaries of functional cancer genomics and potentially uncovering novel therapeutic targets in previously unexplored regulatory regions.
2023-06-30 | GSE200302 | GEO
Project description:Stem cell differentiation depends on transcription factors that are often encoded by mRNAs with highly conserved 3′UTRs. To determine their functional roles, we performed 3′UTR loss-of-function studies. Partial deletion of endogenous 3′UTRs altered stem cell differentiation efficiency in 7/10 cases. As 6/7 3′UTR deletions did not affect expression level of the encoded proteins, we reveal widespread abundance-independent regulatory roles of 3′UTRs. For example, 3′UTR deletion of CTNNB1, an mRNA that encodes the essential Wnt co-activator β-catenin, keeps β-catenin levels unaffected but impairs zebrafish embryogenesis and induction of the Wnt transcriptional program during human stem cell differentiation. We show that long intermolecular 3′UTR-3′UTR interactions between Wnt transcription factor mRNAs and CTNNB1 enable co-translational protein complex assembly of these transcription factors with β-catenin. As antisense oligonucleotide-mediated blocking of 3′UTR interactions impairs Wnt program induction, our findings indicate that transcriptional regulators can form functional units during protein biogenesis to be fully active.
2026-05-05 | GSE329836 | GEO
Project description:Proteomic characterization of prostate cancer cell lines after drug treatment.
2022-10-13 | PXD029525 | Pride
Project description:Profiles of prostate cancer cell lines
| PRJNA343724 | ENA
Project description:The 5′ untranslated region (5′ UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5′ UTR length also plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5′ UTRs enhance leaky scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. Changes in 5′ UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5′ UTR length, including a deletion in the VHL 5′ UTR in von Hippel–Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5′ UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding mutations can reshape the proteome.
2026-01-15 | GSE316181 | GEO