2. Academic Validation
  3. Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

  • J Clin Invest. 2019 Mar 1;129(3):972-987. doi: 10.1172/JCI122779.
Gaoxiang Zhao 1,  Liyan Gong 1,  Dan Su 2,  Yujuan Jin 1,  Chenchen Guo 1,  Meiting Yue 1,  Shun Yao 1,  Zhen Qin 1,  Yi Ye 1 3,  Ying Tang 1,  Qibiao Wu 1,  Jian Zhang 1,  Binghai Cui 1,  Qiurong Ding 4,  Hsinyi Huang 1,  Liang Hu 1,  Yuting Chen 1 3,  Peiyuan Zhang 5,  Guohong Hu 5,  Luonan Chen 1 3,  Kwok-Kin Wong 6,  Daming Gao 1,  Hongbin Ji 1 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
  • 3 School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
  • 4 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 6 Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, USA.
PMID: 30688657 DOI: 10.1172/JCI122779
Abstract

Metastasis is the dominant cause of patient death in small-cell lung Cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1-/- Trp53-/- SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin Ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 Ligase complex and prevented the degradation of Integrin β1, which stabilized Integrin β1 and activated downstream focal adhesion kinase/Src (FAK/Src) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high Integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved Src Inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated Integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

Keywords

Cancer; Lung cancer; Oncology; Ubiquitin-proteosome system.

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