FOXA1 regulates alternative splicing in prostate cancer.
FOXA1 regulates alternative splicing in prostate cancer.
复制标题
DOI：
10.1016/j.celrep.2022.111404
复制
发表时间：
2022-09-27
期刊：
影响因子：
8.8
通讯作者：
Cereda, Matteo
中科院分区：
文献类型：
--
作者：
Del Giudice, Marco;Foster, John G.;Peirone, Serena;Rissone, Alberto;Caizzi, Livia;Gaudino, Federica;Parlato, Caterina;Anselmi, Francesca;Arkell, Rebecca;Guarrera, Simonetta;Oliviero, Salvatore;Basso, Giuseppe;Rajan, Prabhakar;Cereda, Matteo
前列腺癌中选择性剪接的失调与AR、ERG、FOXA 1和MYC激活的转录程序有关。在这里，我们表明FOXA 1作为500个原发性和转移性前列腺癌转录组中选择性剪接失调的主要协调者。我们证明FOXA 1结合剪接相关基因的调控区，包括HNRNPK和SRSF1。通过控制反式作用因子的表达，FOXA 1利用了一种“外显子定义”机制，将选择性剪接校准为显性异构体的产生。这种调节特别影响剪接因子本身，并导致无义介导的衰变（NMD）靶向异构体的减少。FOXA 1控制的癌基因SRSF1包含NMD决定因子FLNA外显子30可促进体外细胞生长并预测疾病复发总的来说，我们报告了FOXA 1在前列腺癌中通过从染色质进入到剪接因子调节，最后到影响患者生存的外显子的选择性剪接的级联事件重新布线选择性剪接景观中的作用。FOXA 1是前列腺癌中剪接因子的主要转录调节因子FOXA 1驱动剪接亚型产生，以达到最佳的主导mRNA产物FOXA 1控制触发NMD的外显子，影响前列腺癌患者预后FOXA 1控制的SRSF 1增强了FLNA外显子30的包含，促进疾病复发Del Giudice等人。确定先驱转录因子FOXA 1作为前列腺癌中选择性剪接的主要调节因子。通过控制剪接因子，FOXA 1缓冲了mRNA显性产物的异构体产生的噪音。这种调节影响无义介导的衰变决定因子外显子的剪接，从而影响患者的生存。
Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an “exon definition” mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival. FOXA1 is a master transcriptional regulator of splicing factors in prostate cancer FOXA1 drives splice isoform production toward an optimal dominant mRNA product FOXA1 controls exons triggering NMD, influencing prostate cancer patient prognosis FOXA1-controlled SRSF1 enhances inclusion of FLNA exon 30, promoting disease recurrence Del Giudice et al. identify the pioneer transcription factor FOXA1 as a master regulator of alternative splicing in prostate cancer. By controlling splicing factors, FOXA1 buffers the noise of isoform production toward a mRNA dominant product. This regulation impacts on splicing of nonsense-mediated decay-determinant exons influencing patient survival.
登录
查看更多内容
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
12.3
作者：
Cereda M;Pozzoli U;Rot G;Juvan P;Schweitzer A;Clark T;Ule J
通讯作者：
Ule J
影响因子：
16
作者：
Feng, Huijuan;Bao, Suying;Zhang, Chaolin
通讯作者：
Zhang, Chaolin