Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.
Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.
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DOI：
10.1016/j.celrep.2022.111443
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发表时间：
2022-10-04
期刊：
影响因子：
8.8
通讯作者：
Okimoto, Ross A.
中科院分区：
文献类型：
--
作者：
Won Kim, Ji;Luck, Cuyler;Wu, Wei;Ponce, Rovingaile Kriska;Lin, Yone Kawe;Gupta, Nehal;Okimoto, Ross A.
Capicua （CIC）失活或yes相关蛋白1 （YAP1）上调可导致多种人类癌症中RAS-RAF-MEK-ERK抑制剂的广泛耐药和肿瘤进展。尽管有这些共同的恶性表型，CIC和YAP1是否存在机制上的联系仍不清楚。本研究表明，erk调控的转录因子CIC可以通过YAP1近端调控元件中的非一致的GGAAGGAA dna结合基序直接抑制YAP1的表达。CIC通过在GGAA重复位点结合，调节正常和人类癌细胞中YAP1的转录输出。在cic缺陷细胞中沉默YAP1可恢复MAPK抑制剂的敏感性并抑制肿瘤生长。因此，我们揭示了人类细胞中MAPK-ERK效应物CIC和YAP1之间的分子联系，并建立了YAP抑制作为靶向CIC缺陷癌症的策略。Kim等人发现，转录抑制因子Capicua （CIC）调节人类癌症中YAP1的表达。cic介导的YAP1抑制通过非一致的GGAA重复基序发生。CIC缺失增加YAP1表达，推动肿瘤进展。YAP抑制cic缺陷癌症克服耐药性，限制肿瘤生长。
Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers. Kim et al. show that the transcriptional repressor Capicua (CIC) regulates YAP1 expression in human cancer. CIC-mediated YAP1 suppression occurs through non-consensus GGAA repeat motifs. CIC loss increases YAP1 expression to drive tumor progression. YAP inhibition in CIC-deficient cancers overcomes drug resistance and limits tumor growth.
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河马效应子YAP促进了对RAF和MEK靶向的癌症疗法的耐药性。
影响因子：
30.8
作者：
Lin L;Sabnis AJ;Chan E;Olivas V;Cade L;Pazarentzos E;Asthana S;Neel D;Yan JJ;Lu X;Pham L;Wang MM;Karachaliou N;Cao MG;Manzano JL;Ramirez JL;Torres JM;Buttitta F;Rudin CM;Collisson EA;Algazi A;Robinson E;Osman I;Muñoz-Couselo E;Cortes J;Frederick DT;Cooper ZA;McMahon M;Marchetti A;Rosell R;Flaherty KT;Wargo JA;Bivona TG
通讯作者：
Bivona TG
影响因子：
64.5
作者：
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DePinho RA
影响因子：
78.8
作者：
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通讯作者：
Schilsky, Richard L.
影响因子：
4.6
作者：
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通讯作者：
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影响因子：
4
作者：
Feng J;Gou J;Jia J;Yi T;Cui T;Li Z
通讯作者：
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