LncRNA OTUD6B-AS1 overexpression induces parthanatos in esophageal adenocarcinoma cells by binding to miR-145-5p and promoting AIF expression.

Objectives

To investigate the functional role of OTU deubiquitinase 6B-antisense transcript 1 (OTUD6B-AS1) and its potential association with parthanatos - a poly (ADP-ribose) polymerase 1 (PARP-1)/apoptosis-inducing factor (AIF)-mediated regulated cell death pathway - in esophageal adenocarcinoma (EAC), which remains poorly understood.

Methods

The expression patterns of OTUD6B-AS1, miR-145-5p, and its downstream target AIF protein were investigated in EAC cell lines. Gain- and loss-of-function assays were performed in vitro and in vivo to evaluate biological effects. The competing endogenous RNA (ceRNA) regulatory mechanism was verified using dual-luciferase reporter assays and RNA immunoprecipitation (RIP) assays. Activation of parthanatos was assessed by detecting AIF nuclear translocation and DNA damage levels. RESULT OTUD6B-AS1 was reduced significantly, and predominantly localized in the cytoplasm of EAC cells. OTUD6B-AS1 overexpression significantly inhibited EAC cell proliferation, migration, and invasion, and induced cellular apoptosis. Mechanistically, OTUD6B-AS1 functioned as a ceRNA, competitively binging to miR-145-5p and thereby relieving its translational suppression of AIF. This biological pathway promoted parthanatos activation, as evidenced by PARP-1 upregulation, extensive DNA damage (with γ-H2AX deposition), and nuclear translocation of AIF. OTUD6B-AS1-induced antitumor activities were abolished by miR-145-5p overexpression or AIF knockdown. Consistently, OTUD6B-AS1 overexpression substantially suppressed xenograft tumor growth in vivo.

Conclusion

OTUD6B-AS1 suppresses EAC progression by sponging miR-145-5p and upregulating AIF to induce parthanatos activation. Targeting this ceRNA regulatory axis may be a therapeutic strategy for EAC.