Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
Department of Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University, Shenyang, 110001, P.R. China.
Signal Transduct Target Ther. 2020 Sep 11;5(1):191. doi: 10.1038/s41392-020-00231-6.
BRAF is the most common genetic alteration and has become a major therapeutic target in thyroid cancers; however, intrinsic feedback mechanism limited clinical use of BRAF specific 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 BRAF in 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 BRAF mutation. CYP2S1 knockdown selectively inhibited cell proliferation, migration, invasion and tumorigenic potential in nude mice, and promoted cell apoptosis in BRAF mutated thyroid cancer cells, but not in BRAF wild-type ones. Mechanistically, BRAF-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 BRAF in thyroid cancer cells, thereby causing synthetic lethal interaction between CYP2S1 and BRAF. Finally, we demonstrated CYP2S1 as a potential therapeutic target in both BRAF-drived xenograft and transgenic mouse models by targetedly delivering CYP2S1-specific siRNA. Altogether, our data demonstrate CYP2S1 as a synthetic lethal partner of BRAF in thyroid cancers, and indicate that targeting CYP2S1 will provide a new therapeutic strategy for BRAF mutated thyroid cancers.
BRAF 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 BRAF 特异性抑制剂的临床应用。合成致死是指两种基因之间的一种相互作用，只有同时干扰这两种基因才能导致致死。在这里，我们鉴定 CYP2S1 为甲状腺癌中 BRAF 的合成致死伙伴。首先，我们发现 CYP2S1 在甲状腺乳头状癌 (PTC) 中表达高于正常甲状腺组织，尤其是在经典型 PTC (CPTC) 和高细胞型 PTC (TCPTC) 中，其表达与 BRAF 突变呈正相关。CYP2S1 敲低选择性地抑制裸鼠中的细胞增殖、迁移、侵袭和致瘤潜能，并促进 BRAF 突变型甲状腺癌细胞中的细胞凋亡，但对 BRAF 野生型细胞没有作用。机制上，BRAF 介导的 MAPK/ERK 级联通过 AHR 依赖性途径上调 CYP2S1 表达，而 CYP2S1 则通过其代谢物增强 AHR 的转录活性。这种 AHR/CYP2S1 反馈回路强烈放大了 BRAF 在甲状腺癌细胞中的致癌作用，从而导致 CYP2S1 和 BRAF 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，在 BRAF 驱动的异种移植和转基因小鼠模型中证明了 CYP2S1 是潜在的治疗靶点。总之，我们的数据表明 CYP2S1 是甲状腺癌中 BRAF 的合成致死伙伴，并表明靶向 CYP2S1 将为 BRAF 突变型甲状腺癌提供新的治疗策略。
