CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers
CYP2S1 is a synthetic lethal target in BRAFV600E-driven thyroid cancers
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CYP2S1 是 BRAFV600E 驱动的甲状腺癌的合成致死靶点
DOI：
10.1038/s41392-020-00231-6
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发表时间：
2020-09-11
影响因子：
39.3
通讯作者：
Hou, Peng
中科院分区：
文献类型：
--
作者：
Li, Yiqi;Su, Xi;Hou, Peng
BRAFV600E是最常见的基因改变，已成为甲状腺癌的主要治疗靶点；然而，内在的反馈机制限制了BRAFV600E特异性抑制剂的临床使用。综合致死是两个基因之间的一种相互作用，只有同时扰乱这两个基因才能导致致死。在这里，我们确定 CYP2S1 是甲状腺癌中 BRAFV600E 的合成致死伙伴。首先，我们发现与正常甲状腺组织相比，CYP2S1在甲状腺乳头状癌（PTC）中高表达，特别是在常规PTC（CPTC）和高细胞PTC（TCPTC）中，并且其表达与BRAFV600E突变呈正相关。 CYP2S1敲低选择性抑制裸鼠细胞的增殖、迁移、侵袭和致瘤潜力，并促进BRAFV600E突变型甲状腺癌细胞的细胞凋亡，但在BRAF野生型细胞中则不然。从机制上讲，BRAFV600E介导的MAPK/ERK级联通过AHR依赖性途径上调CYP2S1的表达，而CYP2S1反过来通过其代谢物增强AHR的转录活性。这种 AHR/CYP2S1 反馈回路强烈放大了 BRAFV600E 在甲状腺癌细胞中的致癌作用，从而导致 CYP2S1 和 BRAFV600E 之间的合成致死相互作用。最后，我们通过靶向递送 CYP2S1 特异性 siRNA，证明 CYP2S1 在 BRAFV600E 驱动的异种移植和转基因小鼠模型中是潜在的治疗靶点。总而言之，我们的数据证明 CYP2S1 作为甲状腺癌中 BRAFV600E 的合成致死伙伴，并表明靶向 CYP2S1 将为 BRAFV600E 突变甲状腺癌提供新的治疗策略。
BRAFV600Eis the most common genetic alteration and has become a major therapeutic target in thyroid cancers; however, intrinsic feedback mechanism limited clinical use of BRAFV600Especific inhibitors. Synthetic lethal is a kind of interaction between two genes, where only simultaneously perturbing both of the genes can lead to lethality. Here, we identified CYP2S1 as a synthetic lethal partner of BRAFV600Ein thyroid cancers. First, we found that CYP2S1 was highly expressed in papillary thyroid cancers (PTCs) compared to normal thyroid tissues, particularly in conventional PTCs (CPTCs) and tall-cell PTCs (TCPTCs), and its expression was positively associated with BRAFV600Emutation. CYP2S1 knockdown selectively inhibited cell proliferation, migration, invasion and tumorigenic potential in nude mice, and promoted cell apoptosis in BRAFV600Emutated thyroid cancer cells, but not in BRAF wild-type ones. Mechanistically, BRAFV600E-mediated MAPK/ERK cascade upregulated CYP2S1 expression by an AHR-dependent pathway, while CYP2S1 in turn enhanced transcriptional activity of AHR through its metabolites. This AHR/CYP2S1 feedback loop strongly amplified oncogenic role of BRAFV600Ein thyroid cancer cells, thereby causing synthetic lethal interaction between CYP2S1 and BRAFV600E. Finally, we demonstrated CYP2S1 as a potential therapeutic target in both BRAFV600E-drived xenograft and transgenic mouse models by targetedly delivering CYP2S1-specific siRNA. Altogether, our data demonstrate CYP2S1 as a synthetic lethal partner of BRAFV600Ein thyroid cancers, and indicate that targeting CYP2S1 will provide a new therapeutic strategy for BRAFV600Emutated thyroid cancers.