BRAFV600E augments WNT signaling in colorectal cancer via aberrant DNA methylation

被引：0

作者：

El Bouazzaoui, Layla ^{[1
,2
,3
]}

Bugter, Jeroen M. ^{[2
]}

Kucukkose, Emre ^{[1
]}

Verheem, Andre ^{[1
]}

Post, Jasmin B. ^{[2
]}

Fenderico, Nicola ^{[2
]}

Rinkes, Inne H. M. Borel ^{[1
]}

Snippert, Hugo J. G. ^{[2
]}

Maurice, Madelon M. ^{[2
,3
]}

Kranenburg, Onno ^{[1
,3
]}

机构：

[1] UMC Utrecht, Div Imaging & Canc, Lab Translat Oncol, Utrecht, Netherlands

[2] UMC Utrecht, Oncode Inst, Ctr Mol Med, Utrecht, Netherlands

[3] Univ Utrecht, Utrecht Platform Organoid Technol, Utrecht, Netherlands

来源：

ISCIENCE | 2025年 / 28卷 / 07期

关键词：

EPIGENETIC INACTIVATION; BRAF MUTATION; RNF43; GENE; DIFFERENTIATION; ACTIVATION; ORGANOIDS; STEMNESS; DISTINCT; GROWTH;

D O I：

10.1016/j.isci.2025.112708

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The BRAF BRAFV600E 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 BRAF (V600E) and RNF43 (P441fs) organoids. BRAF BRAFE600V organoids regained dependency on EGF receptor signaling, and lost tumorigenic potential. Under identical growth conditions, correction of BRAFV600E, rather than RNF43P441fs, 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-associ-ated with transcriptional upregulation- of key WNT effectors (LGR5, EPHB2, and TCF4) in BRAF BRAFV600E organoids. Demethylation treatment resulted in upregulation of WNT antagonists and reduced WNT target gene expression in BRAF BRAFV600E organoids. Our results demonstrate that BRAF BRAFV600E enhances WNT pathway activation through modulation of DNA methylation patterns.

引用

页数：17

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