BRAF通过异常DNA甲基化增强结直肠癌中的WNT信号传导。
BRAF augments WNT signaling in colorectal cancer via aberrant DNA methylation.
作者信息
El Bouazzaoui Layla, Bugter Jeroen M, Küçükköse Emre, Verheem André, Post Jasmin B, Fenderico Nicola, Borel Rinkes Inne H M, Snippert Hugo J G, Maurice Madelon M, Kranenburg Onno
机构信息
Division of Imaging and Cancer, Laboratory Translational Oncology, UMC Utrecht, Utrecht, the Netherlands.
Oncode Institute and Center for Molecular Medicine, UMC Utrecht, Utrecht, the Netherlands.
出版信息
iScience. 2025 May 20;28(7):112708. doi: 10.1016/j.isci.2025.112708. eCollection 2025 Jul 18.
The BRAF mutation drives an aggressive subtype of colorectal cancer (CRC). Although WNT signaling activation is a hallmark of CRC, APC mutations are uncommon in BRAF-V600E mutant CRC, and RNF43 mutations are instead suspected to drive WNT pathway activation. Here, we investigated WNT pathway activation in BRAF-V600E mutant CRC using CRISPR-LbCpf1-corrected (V600E) and (P441fs) organoids. BRAF organoids regained dependency on EGF receptor signaling, and lost tumorigenic potential. Under identical growth conditions, correction of BRAF, rather than RNF43, suppressed WNT target genes and upregulated epithelial differentiation genes and WNT antagonist genes. DNA methylation analysis revealed promoter hypermethylation of WNT antagonist genes and gene body hypermethylation -associated with transcriptional upregulation- of key WNT effectors (LGR5, EPHB2, and TCF4) in BRAF organoids. Demethylation treatment resulted in upregulation of WNT antagonists and reduced WNT target gene expression in BRAF organoids. Our results demonstrate that BRAF enhances WNT pathway activation through modulation of DNA methylation patterns.
BRAF突变驱动结直肠癌（CRC）的一种侵袭性亚型。尽管WNT信号激活是CRC的一个标志，但在BRAF-V600E突变的CRC中，APC突变并不常见，相反，RNF43突变被怀疑驱动WNT通路激活。在此，我们使用CRISPR-LbCpf1校正的（V600E）和（P441fs）类器官研究了BRAF-V600E突变CRC中的WNT通路激活情况。BRAF类器官恢复了对表皮生长因子受体信号的依赖性，并失去了致瘤潜力。在相同的生长条件下，BRAF而非RNF43的校正抑制了WNT靶基因，并上调了上皮分化基因和WNT拮抗剂基因。DNA甲基化分析揭示了BRAF类器官中WNT拮抗剂基因的启动子高甲基化以及关键WNT效应因子（LGR5、EPHB2和TCF4）的与转录上调相关的基因体高甲基化。去甲基化处理导致BRAF类器官中WNT拮抗剂上调，并降低WNT靶基因表达。我们的结果表明，BRAF通过调节DNA甲基化模式增强WNT通路激活。
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