胃癌（GC）是恶性肿瘤的主要原因之一。然而，胃癌发生的分子机制仍不完全清楚。失调的遗传和表观遗传改变对GC的发展有显着影响。在这里，我们报道了 ASH1L 及其反义 lncRNA ASH1L-AS1，它们是从 1q22 处最重要的 GC 风险信号转录而来，充当新的癌基因。 GC标本中ASH1L或lncRNA ASH1L-AS1高水平表达与患者预后较差相关。与此相符，ASH1L 和 ASH1L-AS1 在促进 GC 疾病进展方面具有重要的功能。 LncRNA ASH1L-AS1 上调 ASH1L 转录，增加组蛋白甲基转移酶 ASH1L 表达，并提高 GC 细胞中全基因组 H3K4me3 修饰水平。此外，ASH1L-AS1直接与转录因子NME1蛋白相互作用形成ASH1L-AS1-NME1核糖核蛋白，在转录上促进ASH1L、ASH1L-AS1、KRAS和RAF1的表达，并激活GC细胞中的RAS信号通路。综上所述，我们的数据表明 ASH1L-AS1-ASH1L 调节轴控制癌症中组蛋白修饰重编程和 RAS 信号传导的激活。因此，ASH1L-AS1 可能是临床上 GC 治疗和诊断的新靶点。© 2023。作者，获得 Springer Nature Limited 的独家许可。

Gastric cancer (GC) is one of the most leading cause of malignancies. However, the molecular mechanisms underlying stomach carcinogenesis remain incompletely understood. Dysregulated genetic and epigenetic alternations significantly contribute to GC development. Here, we report that ASH1L and its antisense lncRNA ASH1L-AS1, which are transcribed from the most significant GC-risk signal at 1q22, act as novel oncogenes. The high levels of ASH1L or lncRNA ASH1L-AS1 expression in GC specimens are associated with worse prognosis of patients. In line with this, ASH1L and ASH1L-AS1 are functionally important in promoting GC disease progression. LncRNA ASH1L-AS1 up-regulates ASH1L transcription, increases histone methyltransferase ASH1L expression and elevates genome-wide H3K4me3 modification levels in GC cells. Furthermore, ASH1L-AS1 directly interacts with transcription factor NME1 protein to form the ASH1L-AS1-NME1 ribonucleoprotein, which transcriptionally promotes expression of ASH1L, ASH1L-AS1, KRAS and RAF1, and activates the RAS signaling pathway in GC cells. Taken together, our data demonstrated that the ASH1L-AS1-ASH1L regulatory axis controls histone modification reprogram and activation of the RAS signaling in cancers. Thus, ASH1L-AS1 might be a novel targets of GC therapeutics and diagnosis in the clinic.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.