SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation in pancreatic cancer
Menée in vitro et à l'aide de xénogreffes d'adénocarcinome canalaire du pancréas sur des modèles murins, cette étude met en évidence un mécanisme par lequel le long ARN non codant SLC7A11-AS1, en supprimant la myristoylation de la phosphatase PPM1A, contribue à prolonger l'activation de la voie de signalisation impliquant l'activine A et la protéine Smad et, par conséquent, favorise le développement de cellules souches cancéreuses et la chimiorésistance tumorale
Background : Activin A/Smad signaling plays an important role in promoting cancer stemness and chemoresistance in pancreatic ductal adenocarcinoma (PDAC), however the precise regulation on the termination of this pathway has not been fully understood.
Methods : LncRNA SLC7A11-AS1 interacting proteins were identified through RNA pull-down followed by LC-MS/MS. The protein interaction was analyzed by co-immunoprecipitation. The expressions of SLC7A11-AS1 and activin A in tissue microarray were analyzed by FISH and immunofluerescence. Tumor xenograft mice models were established for in vivo experiments.
Results : Overexpression of SLC7A11-AS1 enhanced the activin A-induced Smad2/3 phosphorylation and promoted cancer stemness properties in PDAC cells. Mechanically, SLC7A11-AS1 interacts with scaffold protein RSL1D1. This interaction disrupts PPM1A myristoylation by suppressing the recruitment of PPM1A and myristoyltransferase NMT1 to RSL1D1, leading to prolonged activation of activin A/Smad signaling through the delay of Smad2/3 dephosphorylation. Co-overexpression of SLC7A11-AS1 and activin A were found in pancreatic patients, and related with the extremely short survival periods. Knockdown of SLC7A11-AS1 and blockade of activin A signaling significantly reduced gemcitabine resistance in PDAC in vitro and in vivo.
Conclusions : SLC7A11-AS1 contributes to prolonged activation of activin A/Smad signaling by suppressing PPM1A myristoylation. Targeting both SLC7A11-AS1 and activin A may offer a potential therapeutic strategy for overcoming gemcitabine resistance in PDAC.
British Journal of Cancer , résumé, 2025