Steadman Kenneth, You Sungyong, Srinivas Dustin V, Mouakkad Lila, Yan Yiwu, Kim Minhyung, Venugopal Smrruthi V, Tanaka Hisashi, Freeman Michael R
Division of Cancer Biology and Therapeutics, Biomedical Sciences and Pathology and Laboratory Medicine, Department of Urology, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, United States.
Front Cell Dev Biol. 2023 Jul 5;11:1206259. doi: 10.3389/fcell.2023.1206259. eCollection 2023.
The transcription factor ONECUT2 (OC2) is a master transcriptional regulator operating in metastatic castration-resistant prostate cancer that suppresses androgen receptor 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 OC2 mRNA suggests that it is a potent master competing endogenous RNA (ceRNA) capable of sequestering miRNAs. Here, we describe a novel role for 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 and then confirmed in prostate cancer cell lines. Genes regulated by OC2 3' UTR exhibited high overlap (up to 45%) with genes driven by the overexpression of the OC2 protein in the absence of 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 3' UTR showed increased polycomb-repressive complex activity. The expression of OC2 3' UTR mRNA alone (without protein) dramatically increased the metastatic potential by assays. Additionally, OC2 3' UTR increased the 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 and a master ceRNA that promotes and protects the same transcriptional network.
转录因子ONECUT2（OC2）是转移性去势抵抗性前列腺癌中的主要转录调节因子，可抑制雄激素受体活性，促进神经分化和肿瘤细胞存活。OC2 mRNA拥有一个异常长（14,575 nt）、进化上保守的3'非翻译区（3'UTR），带有许多微小RNA结合位点，包括多达26个miR-9位点。这一点值得注意，因为miR-9靶向许多受OC2蛋白调控的相同基因。矛盾的是，在miR-9高表达的组织中OC2表达也很高。OC2 mRNA的长度和复杂二级结构表明它是一种强大的主要竞争性内源RNA（ceRNA），能够隔离微小RNA。在此，我们描述了OC2 3'UTR在致命性前列腺癌中的新作用，这与它作为ceRNA的功能一致。通过计算构建了OC2驱动肿瘤中一个合理的ceRNA网络，然后在前列腺癌细胞系中得到证实。受OC2 3'UTR调控的基因与在没有3'UTR情况下OC2蛋白过表达所驱动的基因表现出高度重叠（高达45%），表明OC2蛋白与其3'UTR之间存在协同功能关系。这些重叠网络提示了一种进化上保守的机制，通过保护OC2调控的mRNA免受微小RNA抑制来增强OC2转录。蛋白质和3'UTR都显示出多梳抑制复合物活性增加。单独的OC2 3'UTR mRNA（无蛋白质）的表达通过检测显著增加了转移潜能。此外，OC2 3'UTR增加了负责改变雄激素合成途径的醛酮还原酶和尿苷二磷酸葡萄糖醛酸转移酶家族基因的表达。ONECUT2代表了首个被描述的双模态转录本，它既是驱动去势抵抗性前列腺癌的关键转录因子，又是促进和保护同一转录网络的主要ceRNA。
