CUL4 E3 ligase regulates the proliferation and apoptosis of lung squamous cell carcinoma and small cell lung carcinoma

Cancer Biol Med. 2020 May 15;17(2):357-370. doi: 10.20892/j.issn.2095-3941.2019.0107.

Abstract

Objective: The E3 ligase, CRL4, plays diverse roles in different cellular processes, such as DNA damage, transcriptional regulation, cell cycle progression, and cell apoptosis. Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma (SCC) and small cell lung carcinoma (SCLC). This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC. Methods: We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC, and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot, immunohistochemical staining, flow cytometry, and enzyme inhibition experiments. Results: We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells. CUL4Aknockdown but not CUL4Bknockdown arrested cells in G1 phase while upregulating P21 and CUL4Bknockdown promoted cell apoptosis through upregulation of FOXO3A. Accordingly, CUL4B decreased FOXO3A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome pathway. Conclusions: These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation, which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase, CRL4.

Keywords: CUL4A; CUL4B; FOXO3A; P21; Squamous cell lung cancer; small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Carcinoma, Squamous Cell / enzymology*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Forkhead Box Protein O3 / metabolism
  • Humans
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology
  • Small Cell Lung Carcinoma / enzymology*
  • Small Cell Lung Carcinoma / pathology
  • Survival Analysis
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Up-Regulation

Substances

  • CUL4A protein, human
  • CUL4B protein, human
  • Cullin Proteins
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Ubiquitin-Protein Ligases