2. Academic Validation
  3. CPSF6-mediated XBP1 3'UTR shortening attenuates cisplatin-induced ER stress and elevates chemo-resistance in lung adenocarcinoma

CPSF6-mediated XBP1 3'UTR shortening attenuates cisplatin-induced ER stress and elevates chemo-resistance in lung adenocarcinoma

  • Drug Resist Updat. 2023 May:68:100933. doi: 10.1016/j.drup.2023.100933.
Chuandong Zhu 1,  Yufeng Xie 2,  Qiang Li 3,  Zhiwei Zhang 2,  Juan Chen 4,  Kai Zhang 4,  Xuefeng Xia 5,  Danlei Yu 6,  Dongqin Chen 7,  Zhengyuan Yu 8,  Jing Chen 9
Affiliations

Affiliations

  • 1 Department of Oncology, the Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
  • 2 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
  • 3 Department of Chemotherapy, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330006, China.
  • 4 Department of Respiratory Medicine, Nanjing First Hospital, Nanjing, Medical University, Nanjing 210006, Jiangsu, China.
  • 5 GenePlus-Beijing Institute, Beijing, China.
  • 6 Department of Medical Oncology, the First Affiliated Hospital of Soochow University, No.188 Shizi Street, Gusu District, Suzhou 215006, Jiangsu, China.
  • 7 Department of Medical Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Pudong New District, Shanghai 200127, China; Department of Oncology, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, No. 666, Shengli Road, Nantong 226000, Jiangsu, China. Electronic address: [email protected].
  • 8 Department of Medical Oncology, the First Affiliated Hospital of Soochow University, No.188 Shizi Street, Gusu District, Suzhou 215006, Jiangsu, China. Electronic address: [email protected].
  • 9 Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, No.138 Xianlin Avenue, Nanjing 210023, Jiangsu, China. Electronic address: [email protected].
PMID: 36821972 DOI: 10.1016/j.drup.2023.100933
Abstract

Alternative polyadenylation (APA) is a widespread mechanism generating RNA molecules with alternative 3' ends. Herein, we discovered that TargetScan includes a novel XBP1 transcript with a longer 3' untranslated region (UTR) (XBP1-UL) than that included in NCBI. XBP1-UL exhibited a lowered level in blood samples from lung adenocarcinoma (LUAD) patients and in those after DDP treatment. Consistently, XBP1-UL was reduced in A549 cells compared to normal BEAS-2B cells, as well as in DDP-treated/resistant A549 cells relative to controls. Moreover, due to decreased usage of the distal polyadenylation site (PAS) in 3'UTR, XBP1-UL level was lowered in A549 cells and decreased further in DDP-resistant A549 (A549/DDP) cells. Importantly, use of the distal PAS (dPAS) and XBP1-UL level were gradually reduced in A549 cells under increasing concentrations of DDP, which was attributed to DDP-induced endoplasmic reticulum (ER) stress. Furthermore, XBP1 transcripts with shorter 3'UTR (XBP1-US) were more stable and presented stronger potentiation on DDP resistance. The choice of proximal PAS (pPAS) was attributed to CPSF6 elevation, which was caused by BRCA1-distrupted R-loop accumulation in CPSF6 5'end. DDP-induced nuclear LINC00221 also facilitated CPSF6-induced pPAS choice in the pre-XBP1 3'end. Finally, we found that unlike the unspliced XBP1 protein (XBP1-u), the spliced form XBP1-s retarded p53 degradation to facilitate DNA damage repair of LUAD cells. The current study provides new insights into tumor progression and DDP resistance in LUAD, which may contribute to improved LUAD treatment.

Keywords

Alternative polyadenylation; CPSF6; DDP resistance; LINC00221; Polyadenylation site choice; XBP1.

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