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Genome-wide maps in MCF-7 cells with six2 or CYP4Z1 3'UTR or CYP4Z2P 3'UTR overexpression or not

ABSTRACT: Analysis of MCF-7 cells following six2 or CYP4Z1 3'UTR or CYP4Z2P 3'UTR overexpression. Overexpression of six2 or CYP4Z1 3'UTR or CYP4Z2P 3'UTR positively regulates the abundance of embryonic stem cell function. Results provide insight into the role of six2 mediated-regulation on the ceRNA network between CYP4Z1 and pseudogene CYP4Z2P in breast cancer stemness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116984 | GEO | 2019/03/10

REPOSITORIES: GEO

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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

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Genome-wide maps in MCF-7 cells with six2 or CYP4Z1 3'UTR or CYP4Z2P 3'UTR overexpression or not

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