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CSTF3 通过长链非编码 RNA NEAT1 的可变多聚腺苷酸化和产生短亚型 NEAT1_1 促进卵巢癌铂耐药。

CSTF3 contributes to platinum resistance in ovarian cancer through alternative polyadenylation of lncRNA NEAT1 and generating the short isoform NEAT1_1.

机构信息

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.

出版信息

Cell Death Dis. 2024 Jun 19;15(6):432. doi: 10.1038/s41419-024-06816-1.

DOI:10.1038/s41419-024-06816-1
PMID:38898019
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11187223/
Abstract

Platinum-based chemotherapy is the standard postoperative adjuvant treatment for ovarian cancer (OC). Despite the initial response to chemotherapy, 85% of advanced OC patients will have recurrent disease. Relapsed disease and platinum resistance are the major causes of death in OC patients. In this study, we compared the global regulation of alternative polyadenylation (APA) in platinum-resistant and platinum-sensitive tissues of OC patients by analyzing a set of single-cell RNA sequencing (scRNA-seq) data from public databases and found that platinum-resistant patients exhibited global 3' untranslated region (UTR) shortening due to the different usage of polyadenylation sites (PASs). The APA regulator CSTF3 was the most significantly upregulated gene in epithelial cells of platinum-resistant OC. CSTF3 knockdown increased the sensitivity of OC cells to platinum. The lncRNA NEAT1 has two isoforms, short (NEAT1_1) and long (NEAT1_2) transcript, because of the APA processing in 3'UTR. We found that CSTF3 knockdown reduced the usage of NEAT1 proximal PAS to lengthen the transcript and facilitate the expression of NEAT1_2. Downregulation of the expression of NEAT1 (NEAT1_1/_2), but not only NEAT1_2, also increased the sensitivity of OC cells to platinum. Overexpressed NEAT1_1 reversed the platinum resistance of OC cells after knocking down CSTF3 expression. Furthermore, downregulated expression of CSTF3 and NEAT1_1, rather than NEAT1_2, was positively correlated with inactivation of the PI3K/AKT/mTOR pathway in OC cells. Together, our findings revealed a novel mechanism of APA regulation in platinum-resistant OC. CSTF3 directly bound downstream of the NEAT1 proximal PAS to generate the short isoform NEAT1_1 and was conducive to platinum resistance, which provides a potential biomarker and therapeutic strategy for platinum-resistant OC patients.

摘要

铂类化疗是卵巢癌 (OC) 术后标准辅助治疗。尽管对化疗有初始反应，但 85%的晚期 OC 患者会出现疾病复发。复发疾病和铂耐药性是 OC 患者死亡的主要原因。在这项研究中，我们通过分析来自公共数据库的一组单细胞 RNA 测序 (scRNA-seq) 数据，比较了铂耐药和铂敏感 OC 患者的可变多聚腺苷酸化 (APA) 的全局调控，发现铂耐药患者由于多聚腺苷酸化位点 (PAS) 的不同使用而表现出全局 3'非翻译区 (UTR) 缩短。APA 调节剂 CSTF3 是上皮细胞中上调最显著的基因。CSTF3 敲低增加了 OC 细胞对铂的敏感性。lncRNA NEAT1 有两个亚型，短 (NEAT1_1) 和长 (NEAT1_2) 转录本，是由于 3'UTR 中的 APA 加工。我们发现 CSTF3 敲低减少了 NEAT1 近端 PAS 的使用，从而延长了转录本并促进了 NEAT1_2 的表达。下调 NEAT1 的表达（NEAT1_1/2），而不仅仅是 NEAT1_2，也增加了 OC 细胞对铂的敏感性。过表达 NEAT1_1 逆转了 CSTF3 表达敲低后 OC 细胞的铂耐药性。此外，下调 CSTF3 和 NEAT1_1 的表达，而不是 NEAT1_2 的表达，与 OC 细胞中 PI3K/AKT/mTOR 通路失活呈正相关。总之，我们的研究结果揭示了铂耐药 OC 中 APA 调控的新机制。CSTF3 直接结合在 NEAT1 近端 PAS 的下游，产生短的 NEAT1_1 亚型，有利于铂耐药性，为铂耐药 OC 患者提供了一个潜在的生物标志物和治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/0d068e485f0f/41419_2024_6816_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/ce488df7a2fd/41419_2024_6816_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/042305b38883/41419_2024_6816_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/9e83dbb2ee61/41419_2024_6816_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/07b63f1f80b7/41419_2024_6816_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/bbc43471be55/41419_2024_6816_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/ef0bab77449d/41419_2024_6816_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/9f37d58481a5/41419_2024_6816_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/0d068e485f0f/41419_2024_6816_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/ce488df7a2fd/41419_2024_6816_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/042305b38883/41419_2024_6816_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/9e83dbb2ee61/41419_2024_6816_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/07b63f1f80b7/41419_2024_6816_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/bbc43471be55/41419_2024_6816_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/ef0bab77449d/41419_2024_6816_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/9f37d58481a5/41419_2024_6816_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc90/11187223/0d068e485f0f/41419_2024_6816_Fig8_HTML.jpg

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