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

Tin-Lok Wong, Jia-Jian Loh, Shixun Lu, Helen H. N. Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max J. F. Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jing-Ping Yun, Suet Yi Leung and Stephanie Ma ()
Additional contact information
Tin-Lok Wong: The University of Hong Kong
Jia-Jian Loh: The University of Hong Kong
Shixun Lu: Sun Yat-Sen University Cancer Centre
Helen H. N. Yan: Queen Mary Hospital
Hoi Cheong Siu: Queen Mary Hospital
Ren Xi: National University of Singapore
Dessy Chan: Queen Mary Hospital
Max J. F. Kam: The University of Hong Kong
Lei Zhou: The University of Hong Kong
Man Tong: The University of Hong Kong
John A. Copland: Mayo Clinic Florida
Leilei Chen: National University of Singapore
Jing-Ping Yun: Sun Yat-Sen University Cancer Centre
Suet Yi Leung: Queen Mary Hospital
Stephanie Ma: The University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38581-8

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