<br>FOXO1 促进经典 WNT 靶基因在所检测的基底样乳腺癌和多形性胶质母细胞瘤癌细胞中的表达,FEBS Open Bio

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FOXO1 促进经典 WNT 靶基因在所检测的基底样乳腺癌和多形性胶质母细胞瘤癌细胞中的表达
FEBS Open Bio ( IF 2.8 ) Pub Date : 2023-08-16 , DOI: 10.1002/2211-5463.13696
Shania Pintor ₁ , Alma Lopez ₁ , David Flores ₁ , Brianda Lozoya ₁ , Bipul Soti ₁ , Rishi Pokhrel ₁ , Joaquin Negrete ₁ , Michael W Persans ₁ , Robert Gilkerson _{1,

2} , Bonnie Gunn ₁ , Megan Keniry ₁

Affiliation

基底样乳腺癌（BBC）和多形性胶质母细胞瘤（GBM）是侵袭性癌症，预后不良。 BBC 和 GBM 具有类似干细胞的基因表达特征，部分是由叉头框 O (FOXO) 转录因子驱动的。为了进一步了解 FOXO1 在 BBC 中的影响，我们用 AS1842856 处理 BT549 细胞并进行 RNA 测序。 AS1842856 与未磷酸化的 FOXO1 结合并抑制其直接与 DNA 结合的能力。基因集富集分析表明，AS1842856 处理后，一组 WNT 通路靶基因被强烈诱导，包括淋巴增强子结合因子 1 ( LEF1 ) 和转录因子 7 ( TCF7 )。在 AS1842856 处理后，这些相同的基因也在 GBM 细胞系 U87MG、LN18、LN229、A172 和 DBTRG 中被诱导。相比之下，针对FOXO1的后续 RNA 干扰 (RNAi) 导致 BT549 和 U87MG 细胞中LEF1和TCF7基因表达减少。与 RNAi 实验一致，CRISPR Cas9 介导的FOXO1破坏降低了 U87MG 细胞中经典 WNT 基因LEF1和TCF7的表达。 FOXO1破坏突变体中TCF7基因表达的丧失可以通过 DNA 结合缺陷的FOXO1-H215R的外源表达来恢复。因此，FOXO1 以不依赖 DNA 结合的方式诱导TCF7 ，类似于其他已发表的 FOXO1 激活基因，例如TCF4和 hes 家族 bHLH 转录因子 1。我们的工作表明， FOXO1在所检查的 BBC 和 GBM 细胞中促进经典 WNT 基因表达，与果蝇、T 细胞发育和小鼠急性髓系白血病模型中发现的结果相似。

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FOXO1 promotes the expression of canonical WNT target genes in examined basal-like breast and glioblastoma multiforme cancer cells

Basal-like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem cell-like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis indicated that a set of WNT pathway target genes, including lymphoid enhancer-binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172, and DBTRG upon AS1842856 treatment. By contrast, follow-up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9-mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA-binding-deficient FOXO1-H215R. Therefore, FOXO1 induces TCF7 in a DNA-binding-independent manner, similar to other published FOXO1-activated genes such as TCF4 and hes family bHLH transcription factor 1. Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T-cell development, and murine acute myeloid leukemia models.

更新日期：2023-08-16

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