APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly

Adv Sci (Weinh). 2022 Oct;9(28):e2201889. doi: 10.1002/advs.202201889. Epub 2022 Aug 17.


Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease-activating factor 1 (APAF1)-binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA-binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3-mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase-9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.

Keywords: ABL; IGF2BP1; apoptosis; apoptotic protease-activating factor 1 (APAF1); drug resistance; gastric cancer; m6A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosomes / metabolism
  • Apoptotic Protease-Activating Factor 1 / genetics
  • Apoptotic Protease-Activating Factor 1 / metabolism
  • Biomarkers
  • Caspase 9 / metabolism
  • Cytochromes c / metabolism
  • Cytochromes c / therapeutic use
  • Drug Resistance, Multiple
  • Humans
  • Methyltransferases / metabolism
  • Methyltransferases / therapeutic use
  • RNA, Long Noncoding* / genetics
  • RNA, Small Interfering / therapeutic use
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism


  • APAF1 protein, human
  • Apoptosomes
  • Apoptotic Protease-Activating Factor 1
  • Biomarkers
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Cytochromes c
  • Methyltransferases
  • METTL3 protein, human
  • Caspase 9