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RB1 基因突变导致 YAP 沉默对小细胞肺癌转移至关重要。

YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis.

机构信息

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.

Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.

出版信息

Nat Commun. 2023 Sep 22;14(1):5916. doi: 10.1038/s41467-023-41585-z.

DOI:10.1038/s41467-023-41585-z
PMID:37739954
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10516997/
Abstract

Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis. Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP expression is key for SCLC cells to acquire rapid ameboid migration and high metastatic potential. YAP functions through its target genes CCN1/CCN2 to inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional silencing via E2F7, which recruits the RCOR co-repressor complex to YAP promoter. We discover that benzamide family HDAC inhibitors stimulate YAP expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC metastasis and improving survival in a mouse model. Our study unveils the molecular and cellular basis underlying SCLC's high metastatic potential, the previously unrecognized role of YAP in suppressing ameboid migration and tumor metastasis, and the mechanism of YAP transcription regulation involving E2F7, RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides for SCLC treatment.

摘要

小细胞肺癌（SCLC）由于其普遍的转移而具有高度致命性。大多数 SCLC 都存在 TP53 和 RB1 的失活突变。我们发现 YAP 表达的缺失是 SCLC 细胞获得快速阿米巴样迁移和高转移潜能的关键。YAP 通过其靶基因 CCN1/CCN2 发挥作用，抑制 SCLC 阿米巴样迁移。RB1 突变通过 E2F7 导致 YAP 转录沉默，E2F7 招募 RCOR 共抑制复合物到 YAP 启动子。我们发现苯甲酰胺类 HDAC 抑制剂通过抑制 RCOR-HDAC 复合物刺激 YAP 表达，从而抑制 SCLC 转移并改善小鼠模型中的生存。我们的研究揭示了 SCLC 高转移潜能的分子和细胞基础，揭示了 YAP 在抑制阿米巴样迁移和肿瘤转移中的先前未被认识的作用，以及涉及 E2F7、RCOR 和 Sin3 HDAC 的 YAP 转录调节机制。这项研究揭示了苯甲酰胺类药物治疗 SCLC 的治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/4a1e7fd36bb7/41467_2023_41585_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/566544c61785/41467_2023_41585_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/19bc7d4540d5/41467_2023_41585_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/36c1a2d6de77/41467_2023_41585_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/313fc4836f50/41467_2023_41585_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/8a27fa27424d/41467_2023_41585_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/4a1e7fd36bb7/41467_2023_41585_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/566544c61785/41467_2023_41585_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/19bc7d4540d5/41467_2023_41585_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/36c1a2d6de77/41467_2023_41585_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/313fc4836f50/41467_2023_41585_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/8a27fa27424d/41467_2023_41585_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34d8/10516997/4a1e7fd36bb7/41467_2023_41585_Fig6_HTML.jpg

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