Wang Hao, Guan Tianwang, Hu Rong, Huang Zhongjie, Liang Zhao, Lin Xiaonan, Qiu Yingqi, Liao Peiyun, Guo Xiongbo, Ke Yushen, Zhang Honghao, Ou Caiwen, Li Yuhua
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Guangdong Engineering Research Center of Precision Immune Cell Therapy Technology, Guangzhou, 510280, China.
Theranostics. 2025 Jan 2;15(4):1478-1495. doi: 10.7150/thno.106085. eCollection 2025.
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. 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 using mouse subcutaneous tumor and lung metastasis models. 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. 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. 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.
结直肠癌（CRC）是癌症相关死亡的主要原因。表观遗传修饰在CRC的进展中起重要作用。组蛋白乙酰转移酶KAT7在CRC中的作用尚不清楚。在本研究中，我们使用GEO数据库、蛋白质免疫印迹法和免疫组织化学分析了CRC患者中KAT7的表达及其与预后的相关性。我们通过细胞活力、集落形成、流式细胞术、划痕试验和Transwell试验评估了KAT7对CRC细胞功能的影响。通过RNA测序和染色质免疫沉淀-定量聚合酶链反应获得了机制方面的见解。此外，我们使用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。在本研究中，我们发现CRC中KAT7信号通路上调及其与患者不良生存的关联。敲低KAT7可促进CRC细胞凋亡并抑制其增殖、迁移和侵袭。相反，KAT7过表达增强了这些细胞过程。试验证实敲低KAT7可抑制CRC增殖和肺转移。机制上，KAT7使组蛋白H3赖氨酸14（H3K14）乙酰化以增强MRAS转录，从而激活MAPK/ERK途径并促进肿瘤发生。KAT7作为乙酰转移酶的酶功能对于结直肠癌的进展至关重要。在敲低KAT7的CRC细胞中，重新表达KAT7而非缺乏乙酰转移酶活性的突变体可挽救MRAS表达、ERK磷酸化和CRC肿瘤发生。我们发现KAT7在CRC患者中高表达，且KAT7高表达的患者预后较差。KAT7通过促进H3K14乙酰化增强MRAS基因转录，从而激活MAPK/ERK途径并促进CRC的恶性表型。总之，KAT7是CRC治疗的一个有前景的靶点。
