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.
Similar content being viewed by others
Data availability
The primary datasets generated in this study are available in Genome Sequence Archive-human HRA003621 (https://ngdc.cncb.ac.cn/gsa-human/).
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396:635–48.
Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71:264–79.
Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24:1449–58.
Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol. 2020;18:534–42.
Yeoh KG, Tan P. Mapping the genomic diaspora of gastric cancer. Nat Rev Cancer. 2022;22:71–84.
Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol. 2017;14:467–78.
Zheng Y, Lei T, Jin G, Guo H, Zhang N, Chai J, et al. LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5. EMBO Rep. 2021;22:e52707.
Zhang H, Ma RR, Zhang G, Dong Y, Duan M, Sun Y, et al. Long noncoding RNA lnc-LEMGC combines with DNA-PKcs to suppress gastric cancer metastasis. Cancer Lett. 2022;524:82–90.
Zhou M, Dong J, Huang J, Ye W, Zheng Z, Huang K, et al. Chitosan-gelatin-EGCG nanoparticle-meditated LncRNA TMEM44-AS1 silencing to activate the P53 signaling pathway for the synergistic reversal of 5-FU resistance in gastric cancer. Adv Sci. 2022;9:e2105077.
Li ZY, Xie Y, Deng M, Zhu L, Wu X, Li G, et al. c-Myc-activated intronic miR-210 and lncRNA MIR210HG synergistically promote the metastasis of gastric cancer. Cancer Lett. 2022;526:322–34.
Zhang N, Wang B, Ma C, Zeng J, Wang T, Han L, et al. LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization. J Exp Clin Cancer Res. 2023;42:89.
Hu F, Peng Y, Chang S, Luo X, Yuan Y, Zhu X, et al. Vimentin binds to a novel tumor suppressor protein, GSPT1-238aa, encoded by circGSPT1 with a selective encoding priority to halt autophagy in gastric carcinoma. Cancer Lett. 2022;545:215826.
Dai T, Zhang X, Zhou X, Hu X, Huang X, Xing F, et al. Long non-coding RNA VAL facilitates PKM2 enzymatic activity to promote glycolysis and malignancy of gastric cancer. Clin Transl Med. 2022;12:e1088.
Wang S, Wo L, Zhang Z, Zhu C, Wang C, Wang Y, et al. Delivery of LINC00589 via mesoporous silica nanoparticles inhibits peritoneal metastasis in gastric cancer. Cancer Lett. 2022;549:215916.
Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.
Chen X, Xie R, Gu P, Huang M, Han J, Dong W, et al. Long noncoding RNA LBCS inhibits self-renewal and chemoresistance of bladder cancer stem cells through epigenetic silencing of SOX2. Clin Cancer Res. 2019;25:1389–403.
Li Y, Liu X, Cui X, Tan Y, Wang Q, Wang Y, et al. LncRNA PRADX-mediated recruitment of PRC2/DDX5 complex suppresses UBXN1 expression and activates NF-kappaB activity, promoting tumorigenesis. Theranostics. 2021;11:4516–30.
Saeki N, Saito A, Choi IJ, Matsuo K, Ohnami S, Totsuka H, et al. A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology. 2011;140:892–902.
Shi Y, Hu Z, Wu C, Dai J, Li H, Dong J, et al. A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1. Nat Genet. 2011;43:1215–8.
Hu N, Wang Z, Song X, Wei L, Kim BS, Freedman ND, et al. Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours. Gut. 2016;65:1611–8.
Wang Z, Dai J, Hu N, Miao X, Abnet CC, Yang M, et al. Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies. Gut. 2017;66:581–7.
Tanikawa C, Kamatani Y, Toyoshima O, Sakamoto H, Ito H, Takahashi A, et al. Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21. Cancer Sci. 2018;109:4015–24.
Jin G, Lv J, Yang M, Wang M, Zhu M, Wang T, et al. Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study. Lancet Oncol. 2020;21:1378–86.
Desvignes T, Pontarotti P, Fauvel C, Bobe J. Nme protein family evolutionary history, a vertebrate perspective. BMC Evol Biol. 2009;9:256.
Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 1988;80:200–4.
Curtis CD, Likhite VS, McLeod IX, Yates JR, Nardulli AM. Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression. Cancer Res. 2007;67:10600–7.
Cervoni L, Egistelli L, Eufemi M, Scotto d’Abusco A, Altieri F, Lascu I, et al. DNA sequences acting as binding sites for NM23/NDPK proteins in melanoma M14 cells. J Cell Biochem. 2006;98:421–8.
Choudhuri T, Verma SC, Lan K, Robertson ES. Expression of alpha V integrin is modulated by Epstein-Barr virus nuclear antigen 3C and the metastasis suppressor Nm23-H1 through interaction with the GATA-1 and Sp1 transcription factors. Virology. 2006;351:58–72.
Osada H, Tomida S, Yatabe Y, Tatematsu Y, Takeuchi T, Murakami H, et al. Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res. 2008;68:1647–55.
Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM, et al. Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 2012;22:2315–27.
Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 2014;509:91–95.
Mouradov D, Sloggett C, Jorissen RN, Love CG, Li S, Burgess AW, et al. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. Cancer Res. 2014;74:3238–47.
Shen Y, Zhang N, Chai J, Wang T, Ma C, Han L, et al. CircPDIA4 induces gastric cancer progression by promoting ERK1/2 activation and enhancing biogenesis of oncogenic circRNAs. Cancer Res. 2023;83:538–52.
Sang L, Ju HQ, Yang Z, Ge Q, Zhang Z, Liu F, et al. Mitochondrial long non-coding RNA GAS5 tunes TCA metabolism in response to nutrient stress. Nat Metab. 2021;3:90–106.
Toki N, Takahashi H, Sharma H, Valentine MNZ, Rahman FM, Zucchelli S, et al. SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies. Nucleic Acids Res. 2020;48:11626–44.
Mitra S, Muralidharan SV, Di Marco M, Juvvuna PK, Kosalai ST, Reischl S, et al. Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma. Cancer Res. 2021;81:1457–71.
Lu C, Liu Z, Klement JD, Yang D, Merting AD, Poschel D et al. WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape. J Immunother Cancer. 2021;9:e002624.
Yu J, Zheng W. An alternative method for screening gastric cancer based on serum levels of CEA, CA19-9, and CA72-4. J Gastrointest Cancer. 2018;49:57–62.
Gregory GD, Vakoc CR, Rozovskaia T, Zheng X, Patel S, Nakamura T, et al. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol Cell Biol. 2007;27:8466–79.
Qin L, Williams JB, Tan T, Liu T, Cao Q, Ma K, et al. Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures. Nat Commun. 2021;12:6589.
Brinkmeier ML, Geister KA, Jones M, Waqas M, Maillard I, Camper SA. The histone methyltransferase gene absent, small, or homeotic discs-1 like is required for normal hox gene expression and fertility in mice. Biol Reprod. 2015;93:121.
Ruiz-Orera J, Messeguer X, Subirana JA, Alba MM. Long non-coding RNAs as a source of new peptides. Elife. 2014;3:e03523.
Anderson DM, Anderson KM, Chang CL, Makarewich CA, Nelson BR, McAnally JR, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160:595–606.
Sousa ME, Farkas MH. Micropeptide. PLoS Genet. 2018;14:e1007764.
Sun L, Wang W, Han C, Huang W, Sun Y, Fang K, et al. The oncomicropeptide APPLE promotes hematopoietic malignancy by enhancing translation initiation. Mol Cell. 2021;81:4493–4508.e4499.
Liu J, Zhang N, Zeng J, Wang T, Shen Y, Ma C, et al. N(6) -methyladenosine-modified lncRNA ARHGAP5-AS1 stabilises CSDE1 and coordinates oncogenic RNA regulons in hepatocellular carcinoma. Clin Transl Med. 2022;12:e1107.
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).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-023-02855-8
- Springer Nature Limited