Targeting KAT7 inhibits the progression of colorectal cancer.

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Theranostics Pub Date : 2025-01-02 eCollection Date: 2025-01-01 DOI:10.7150/thno.106085
Hao Wang, Tianwang Guan, Rong Hu, Zhongjie Huang, Zhao Liang, Xiaonan Lin, Yingqi Qiu, Peiyun Liao, Xiongbo Guo, Yushen Ke, Honghao Zhang, Caiwen Ou, Yuhua Li
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Abstract

Rationale: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Epigenetic modifications play a significant role in the progression of CRC. KAT7, a histone acetyltransferase, has an unclear role in CRC. Methods: In this research, we analyzed the expression of KAT7 in CRC patients and its correlation with prognosis using the GEO database, western blot, and immunohistochemistry. We assessed the impact of KAT7 on CRC cell functions through cell viability, colony formation, flow cytometry, scratch, and transwell assays. Mechanistic insights were obtained via RNA sequencing and ChIP-qPCR. Additionally, we evaluated the effects of KAT7 on CRC growth and metastasis in vivo using mouse subcutaneous tumor and lung metastasis models. Results: In this study, we discovered an upregulated KAT7 signaling pathway in CRC and its association with poor patient survival. Knockdown of KAT7 promotes apoptosis and inhibits proliferation, migration, and invasion of CRC cells. Conversely, KAT7 overexpression enhanced these cellular processes. In vivo assays confirmed that knockdown of KAT7 can inhibit CRC proliferation and lung metastasis. Mechanistically, KAT7 acetylated histone H3 at lysine 14 (H3K14) to enhance MRAS transcription, which activated the MAPK/ERK pathway and promoted tumorigenesis. The enzymatic function of KAT7 as an acetyltransferase is crucial for the advancement of colorectal cancer. In KAT7 knockdown CRC cells, re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescued MRAS expression, ERK phosphorylation, and CRC tumorigenesis. Conclusion: We found that KAT7 is highly expressed in CRC patients, and those with high KAT7 expression have a worse prognosis. KAT7 enhances MRAS gene transcription by promoting H3K14 acetylation, thereby activating the MAPK/ERK pathway and promoting malignant phenotypes of CRC. In summary, KAT7 represents a promising target for CRC therapy.

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靶向KAT7抑制结直肠癌的进展。
理由:结直肠癌(CRC)是癌症相关死亡的主要原因。表观遗传修饰在结直肠癌的进展中起重要作用。KAT7是一种组蛋白乙酰转移酶,在结直肠癌中的作用尚不清楚。方法:本研究采用GEO数据库、western blot和免疫组织化学分析KAT7在结直肠癌患者中的表达及其与预后的关系。我们通过细胞活力、集落形成、流式细胞术、划痕和transwell试验评估了KAT7对CRC细胞功能的影响。通过RNA测序和ChIP-qPCR获得机制见解。此外,我们通过小鼠皮下肿瘤和肺转移模型评估了KAT7对CRC生长和转移的影响。结果:在本研究中,我们发现了CRC中KAT7信号通路的上调及其与患者生存差的关系。KAT7的下调促进CRC细胞凋亡,抑制CRC细胞的增殖、迁移和侵袭。相反,KAT7过表达增强了这些细胞过程。体内实验证实,KAT7的下调可抑制结直肠癌的增殖和肺转移。机制上,KAT7乙酰化组蛋白H3在赖氨酸14位点(H3K14),增强MRAS转录,激活MAPK/ERK通路,促进肿瘤发生。KAT7作为一种乙酰转移酶的酶功能对结直肠癌的进展至关重要。在KAT7敲除的CRC细胞中,重新表达KAT7,而不是乙酰转移酶缺陷突变体,挽救了MRAS表达,ERK磷酸化和CRC肿瘤发生。结论:我们发现KAT7在结直肠癌患者中高表达,且KAT7高表达者预后较差。KAT7通过促进H3K14乙酰化来增强MRAS基因转录,从而激活MAPK/ERK通路,促进CRC的恶性表型。综上所述,KAT7是CRC治疗的一个有希望的靶点。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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