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The ASH1L-AS1-ASH1L axis controls NME1-mediated activation of the RAS signaling in gastric cancer

Oncogene volume 42, pages 3435–3445 (2023)Cite this article

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Abstract

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.

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Fig. 1: The increased levels of ASH1L and ASH1L-AS1 in GC tissues and the oncogenic role of ASH1L during cancer development.
Fig. 2: LncRNA ASH1L-AS1 promoted the malignant phenotypes of GC cells in vitro and in vivo.
Fig. 3: LncRNA ASH1L-AS1 interacted with onco-protein NME1 and prompted NME1 nucleus detention.
Fig. 4: NME1 acted as a crucial TF to promote expression of ASH1L-AS1 and ASH1L.
Fig. 5: ASH1L-AS1 elevated expression of KRAS and RAF1 and activated the RAS signaling pathway in GC cells.
Fig. 6: Graphical representation of the regulation and functions of lncRNA ASH1L-AS1 in GC.

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Data availability

The primary datasets generated in this study are available in Genome Sequence Archive-human HRA003621 (https://ngdc.cncb.ac.cn/gsa-human/).

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82372760, 82173070 and 82103291); Natural Science Foundation of Shandong Province (ZR2021LZL004 and ZR202102250889); Major Scientific and Technological Innovation Project of Shandong Province (2021ZDSYS04); Taishan Scholars Program of Shandong Province (tsqn202211340 and tstp20221141); Program of Science and Technology for the youth innovation team in universities of Shandong Province (2020KJL001 and 2022KJ316). The authors would like to thank the many individuals who participated in the study. The authors have no conflicts of interest to disclose.

Funding

This work was supported by the National Natural Science Foundation of China (82372760, 82173070 and 82103291); Natural Science Foundation of Shandong Province (ZR2021LZL004 and ZR202102250889); Major Scientific and Technological Innovation Project of Shandong Province (2021ZDSYS04); Taishan Scholars Program of Shandong Province (tsqn202211340 and tstp20221141); Program of Science and Technology for the youth innovation team in universities of Shandong Province (2020KJL001 and 2022KJ316).

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  1. These authors contributed equally: Mengyu Xie, Long Zhang.

Authors and Affiliations

  1. Departemnt of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China

    Mengyu Xie & Nasha Zhang

  2. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China

    Mengyu Xie, Long Zhang, Linyu Han, Linying Huang, Yizhou Huang & Ming Yang

  3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Ming Yang & Nasha Zhang

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Contributions

NZ conceived the project and supervised all experiments. NZ and MY designed the project. MX and LZ performed the experiments. MY, NZ, MX and LZ analyzed the data. LZ, LHan, LHuang and YH collected the human samples. MY, NZ, and LZ drafted the manuscript. MY and NZ critically revised the manuscript for important intellectual content. NZ supervised this study. All authors read and approved the final manuscript.

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Correspondence to Nasha Zhang.

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Xie, M., Zhang, L., Han, L. et al. The ASH1L-AS1-ASH1L axis controls NME1-mediated activation of the RAS signaling in gastric cancer. Oncogene 42, 3435–3445 (2023). https://doi.org/10.1038/s41388-023-02855-8

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