ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer

Abstract

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance.

The predictive accuracy of machine learning for the risk of death in HIV patients: a systematic review and meta-analysis

“…These studies comprised 22 cohort studies [ 31 – 52 ]and 2 nested case-control studies [ 7 – 30 ]. In terms of patient sources, 15 studies originated from multicenter sources [ 31 , 33 – 35 , 37 , 39 , 40 , 42 , 44 – 48 , 50 , 51 , 53 ], 2 were drawn from a registered database [ 13 , 18 ], and 7 were conducted at single centers [ 8 , 10 , 15 , 20 , 23 , 27 , 30 ]. In a follow-up report, one study specifically focused on in-hospital deaths resulting from the combination of Talaromyces marneffei and HIV infection [ 8 ], while the remaining studies reported deaths during long-term follow-up, with the longest follow-up period extending to 36 years [ 7 ].…”

“…The generation of the validation set involved internal random sampling and external validation, with external validation utilizing two modes: prospective and multicenter. The 8 studies employed survival analysis models (COX regression) [ 7 , 9 – 11 , 20 , 23 , 26 , 30 ], while the remaining 16 studies utilized non-survival analysis models [ 32 , 35 – 42 , 44 – 46 , 49 – 51 ]. The modeling variables are detailed in the Additional Materials.…”

RNA editing enzymes: structure, biological functions and applications

“…Substituting A with I in an A-U base pair reduces stability, while introducing I in an A-C mismatch increases stability [ 63 ]. Wone et al demonstrated that A-to-I editing of the 3’ UTR of stearoyl-CoA desaturase (SCD1) increased KHDRBS1 binding, thus enhancing the stability of SCD1 mRNA [ 64 ]. Apart from ADAR1, ADAR2 also binds to and stabilizes RNA in a manner that is independent of editing.…”

Emerging roles of 3D-culture systems in tackling tumor drug resistance

“…As mentioned above, RNA editing is correlated with the emergence of resistance [ 31 ] ; organoid lines from resistant patients with the intestinal subtype of gastric cancer (GC) showed upregulation of JAK/Src-signal transducer and activator of the transcription (STAT) signaling and adenosine deaminases acting on RNA 1 (ADAR1), along with hyper-edited lipid metabolism genes due to A-to-I editing on the 3’UTR of stearoyl- CoA desaturase (SCD1). SCD1 favored lipid droplet formation, reducing chemotherapy-induced ER stress and enhancing self-renewal in resistant GC lines [ 63 ] . In another subset of GC known as stem-like/Epithelial-to-mesenchymal transition/Mesenchymal (SEM-type) GC, resistance to glutaminolysis inhibition was observed due to a stem-like population in the tumor.…”