2. Academic Validation
  3. Specific intracellular retention of circSKA3 promotes colorectal cancer metastasis by attenuating ubiquitination and degradation of SLUG

Specific intracellular retention of circSKA3 promotes colorectal cancer metastasis by attenuating ubiquitination and degradation of SLUG

  • Cell Death Dis. 2023 Nov 16;14(11):750. doi: 10.1038/s41419-023-06279-w.
Jingwen Deng # 1,  Shaoxia Liao # 1,  Chaoyi Chen 2,  Fengyan Han 1,  Siqin Lei 1,  Xuan Lai 1,  Kehong Ye 1,  Qizheng Han 1,  Fang E 1,  Chao Lu 3,  Maode Lai 4 5,  Fanlong Liu 6,  Honghe Zhang 7 8
Affiliations

Affiliations

  • 1 Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), 310058, Hangzhou, China.
  • 2 Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Department of Chemistry, University of South Florida, Tampa, FL, 33620, USA.
  • 4 Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, 310058, Hangzhou, China.
  • 5 Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou, 310058, China.
  • 6 Department of Colorectal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 310058, Hangzhou, China. fanlong_liu@zju.edu.cn.
  • 7 Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), 310058, Hangzhou, China. honghezhang@zju.edu.cn.
  • 8 Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou, 310058, China. honghezhang@zju.edu.cn.
  • # Contributed equally.
PMID: 37973787 DOI: 10.1038/s41419-023-06279-w
Abstract

Our previous study demonstrated that tumor-suppressor circular RNAs (circRNAs) can be specifically secreted outside of colorectal Cancer (CRC) cells within exosomes to maintain tumor cell fitness. However, whether tumor-driving circRNAs can be specifically retained in cells to facilitate tumor progression remains unknown. In this study, circRNA-seq showed that circSKA3 was significantly upregulated in CRC tissues but downregulated in serum samples from CRC patients. In addition, circSKA3 promoted CRC progression in vitro and in vivo and was retained in CRC cells via a specific cellmotif element. Interestingly, the cellmotif element was also the site of interaction of circSKA3 with SLUG, which inhibited SLUG ubiquitination degradation and promoted CRC epithelial-mesenchymal transition (EMT). Moreover, FUS was identified as a key circularization regulator of circSKA3 that bound to the key element. Finally, we designed and synthesized specific Antisense Oligonucleotides (ASOs) targeting circularization and cellmotif elements, which repressed circSKA3 expression, abolished the SLUG-circSKA3 interaction, and further inhibited CRC EMT and metastasis in vitro and in vivo.

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