PDF(Pubmed)
Abstract：
BACKGROUND: m6A modification is currently recognized as a major driver of RNA function that maintains cancer cell homeostasis. Long non-coding (Lnc) RNAs control cell proliferation and play an important role in the occurrence and progression of colorectal cancer (CRC). ZCCHC4 is a newly discovered m6A methyltransferase whose role and mechanism in tumors have not yet been elucidated.
METHODS: The EpiQuik m6A RNA methylation kit was used to detect the level of total RNA m6A in six types of digestive tract tumors. The Kaplan-Meier method and receiver operating characteristic curve were used to evaluate the prognostic and diagnostic value of the newly discovered m6A methyltransferase, ZCCHC4, in CRC. The effects on CRC growth in vitro and in vivo were studied using gain- and loss-of-function experiments. The epigenetic mechanisms underlying ZCCHC4 upregulation in CRC were studied using RIP, MeRIP-seq, RNA pull-down, and animal experiments.
RESULTS: We reported that the ZCCHC4-LncRNAGHRLOS-KDM5D axis regulates the growth of CRC in vitro and in vivo. We found that ZCCHC4 was upregulated in primary CRC samples and could predict adverse clinical outcomes in patients with CRC. Mechanistically, ZCCHC4 downregulated LncRNAGHRLOS to promote CRC tumorigenesis. As a downstream molecule of LncRNAGHRLOS, KDM5D directly controls CRC cell proliferation, migration, and invasion.
CONCLUSIONS: This study suggests that the ZCCHC4 axis contributes to the tumorigenesis and progression of CRC and that ZCCHC4 may be a potential biomarker for this malignancy.
METHODS: The EpiQuik m6A RNA methylation kit was used to detect the level of total RNA m6A in six types of digestive tract tumors. The Kaplan-Meier method and receiver operating characteristic curve were used to evaluate the prognostic and diagnostic value of the newly discovered m6A methyltransferase, ZCCHC4, in CRC. The effects on CRC growth in vitro and in vivo were studied using gain- and loss-of-function experiments. The epigenetic mechanisms underlying ZCCHC4 upregulation in CRC were studied using RIP, MeRIP-seq, RNA pull-down, and animal experiments.
RESULTS: We reported that the ZCCHC4-LncRNAGHRLOS-KDM5D axis regulates the growth of CRC in vitro and in vivo. We found that ZCCHC4 was upregulated in primary CRC samples and could predict adverse clinical outcomes in patients with CRC. Mechanistically, ZCCHC4 downregulated LncRNAGHRLOS to promote CRC tumorigenesis. As a downstream molecule of LncRNAGHRLOS, KDM5D directly controls CRC cell proliferation, migration, and invasion.
CONCLUSIONS: This study suggests that the ZCCHC4 axis contributes to the tumorigenesis and progression of CRC and that ZCCHC4 may be a potential biomarker for this malignancy.
摘要：
背景：m6A修饰目前被认为是维持癌细胞稳态的RNA功能的主要驱动因素。长链非编码(Lnc)RNA控制细胞增殖,在结直肠癌(CRC)的发生和发展中起重要作用。ZCCHC4是一种新发现的m6A甲基转移酶，其在肿瘤中的作用和机制尚未阐明。
方法：使用EpiQuikm6ARNA甲基化试剂盒检测六种消化道肿瘤中总RNAm6A的水平。采用Kaplan-Meier法和受试者工作特征曲线评价新发现的m6A甲基转移酶的预后和诊断价值,ZCCHC4，在CRC中。使用功能增益和功能丧失实验研究了体外和体内对CRC生长的影响。使用RIP研究了CRC中ZCCHC4上调的表观遗传机制，MeRIP-seq,RNA下拉，和动物实验。
结果：我们报道了ZCCHC4-LncRNAGHRLOS-KDM5D轴在体外和体内调节CRC的生长。我们发现ZCCHC4在原发性CRC样本中上调，可以预测CRC患者的不良临床结局。机械上,ZCCHC4下调LncRNAGHRLOS以促进CRC肿瘤发生。作为LncRNAGHRLOS的下游分子，KDM5D直接控制CRC细胞增殖，迁移,和入侵。
结论：本研究提示ZCCHC4轴有助于CRC的肿瘤发生和进展，ZCCHC4可能是该恶性肿瘤的潜在生物标志物。
方法：使用EpiQuikm6ARNA甲基化试剂盒检测六种消化道肿瘤中总RNAm6A的水平。采用Kaplan-Meier法和受试者工作特征曲线评价新发现的m6A甲基转移酶的预后和诊断价值,ZCCHC4，在CRC中。使用功能增益和功能丧失实验研究了体外和体内对CRC生长的影响。使用RIP研究了CRC中ZCCHC4上调的表观遗传机制，MeRIP-seq,RNA下拉，和动物实验。
结果：我们报道了ZCCHC4-LncRNAGHRLOS-KDM5D轴在体外和体内调节CRC的生长。我们发现ZCCHC4在原发性CRC样本中上调，可以预测CRC患者的不良临床结局。机械上,ZCCHC4下调LncRNAGHRLOS以促进CRC肿瘤发生。作为LncRNAGHRLOS的下游分子，KDM5D直接控制CRC细胞增殖，迁移,和入侵。
结论：本研究提示ZCCHC4轴有助于CRC的肿瘤发生和进展，ZCCHC4可能是该恶性肿瘤的潜在生物标志物。
