LncRNA SLC7A11-AS1 promotes chemoresistance by blocking SCFβ-TRCP-mediated degradation of NRF2 in pancreatic cancer

Abstract Drug resistance is the major obstacle of gemcitabine-based chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC). Many long non-coding RNAs (lncRNAs) are reported to play vital roles in cancer initiation and progression. Here, we report that lncRNA SLC7A11-AS1 is involved in gemcitabine resistance of PDAC. SLC7A11-AS1 is overexpressed in PDAC tissues and gemcitabine resistant cell lines. Knockdown of SLC7A11-AS1 weakens the PDAC stemness and potentiates the sensitivity of resistant PDAC cells towards gemcitabine in vitro and in vivo. SLC7A11-AS1 promotes chemoresistance through reducing intracellular reactive oxygen species (ROS) by stabilizing NRF2, the key regulator in antioxidant defense. Mechanically, SLC7A11-AS1 is co-localized with β-TRCP1 in the nucleus. The exon 3 of SLC7A11-AS1 interacts with the F-box motif of β-TRCP1, the critical domain that recruits β-TRCP1 to the SCFβ-TRCP E3 complex. This interaction prevents the consequent ubiquitination and proteasomal degradation of NRF2 in the nucleus. Our results demonstrate that the overexpression of SLC7A11-AS1 in gemcitabine resistant PDAC cells can scavenge ROS by blocking SCFβ-TRCP-mediated ubiquitination and degradation of NRF2, leading to low level of intracellular ROS which is required for the maintenance of cancer stemness. These findings suggest SLC7A11-AS1 as a therapeutic target to overcome gemcitabine resistance for PDAC treatment.