Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway.
Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway.
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DOI：
10.1186/s13046-022-02373-7
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发表时间：
2022-05-07
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影响因子：
--
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三阴性乳腺癌（TNBC）是高度恶性的，与其他亚型的乳腺癌相比，由于缺乏治疗靶点，预后更差。KIF 23在肿瘤发生和癌症进展中起着至关重要的作用。然而，KIF 23在TNBC发展中的作用和潜在机制仍然未知。本研究旨在阐明KIF 23在TNBC中的生物学功能和调控机制。采用实时荧光定量PCR和Western blot检测乳腺癌组织和细胞系中KIF 23的表达。然后，进行体外和体内功能实验，研究KIF 23对TNBC肿瘤生长和转移的影响。进行染色质免疫沉淀测定以说明KIF 23在TNBC中的潜在调节机制。我们发现KIF 23在TNBC中显著上调，并且与不良预后相关。KIF 23在体外和体内均能促进TNBC的增殖、迁移和侵袭。KIF 23可激活Wnt/β-catenin通路，促进TNBC的EMT进展。此外，WDR 5通过H3 K4 me 3修饰上调FOXM 1，FOXM 1直接与KIF 23基因启动子结合，促进其转录，通过Wnt/β-catenin途径加速TNBC进展。FOXM 1和WDR 5的小分子抑制剂均能抑制TNBC的进展。我们的研究结果阐明了WDR 5/FOXM 1/KIF 23/Wnt/β-catenin轴与TNBC进展相关，并可能为TNBC治疗提供新的和有希望的治疗靶点。在线版本包含补充材料，可通过10.1186/s13046-022-02373-7获得。
Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment. The online version contains supplementary material available at 10.1186/s13046-022-02373-7.
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DOI：
10.1083/jcb.200511061
发表时间：
2006-01-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gruneberg U;Neef R;Li X;Chan EH;Chalamalasetty RB;Nigg EA;Barr FA
通讯作者：
Barr FA
影响因子：
--
作者：
Gao CT;Ren J;Yu J;Li SN;Guo XF;Zhou YZ
通讯作者：
Zhou YZ
影响因子：
24.5
作者：
Chen J;Rajasekaran M;Xia H;Zhang X;Kong SN;Sekar K;Seshachalam VP;Deivasigamani A;Goh BK;Ooi LL;Hong W;Hui KM
通讯作者：
Hui KM
影响因子：
3.7
作者：
Fischer M;Grundke I;Sohr S;Quaas M;Hoffmann S;Knörck A;Gumhold C;Rother K
通讯作者：
Rother K
影响因子：
8
作者：
Iltzsche, F.;Simon, K.;Gaubatz, S.
通讯作者：
Gaubatz, S.