A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1-hyperactivated pancreatic cancer

Cell Discovery

Article

Shuyu Zhai¹  Jiayu Lin¹  Yang Liu¹  Yuchen Ji¹  Jia Liu¹  Xiaxing Deng¹  Yusheng Shi¹  Fanlu Li¹  Da Fu¹  Xiaomei Tang¹  Zehui Zhang¹  Ronghao Zhang¹  Baiyong Shen¹  Hongzhe Li¹  Yizhi Cao¹  Pengyi Liu¹  Jiewei Lin² 

[1] Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China;State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China;Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China;

关键词: ;   

DOI  :  10.1038/s41421-023-00592-6

 received in 2023-01-18, accepted in 2023-07-28,  发布年份 2023

来源: Springer

【 摘 要 】

The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis, chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer; however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1 degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and suggest a promising therapeutic strategy targeting the N1DARP–N1ICD interaction in Notch1-activated pancreatic cancer.

【 授权许可】

CC BY   
© Center for Excellence in Molecular Cell Science, CAS 2023

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