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Title: CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR

Journal Article · · Molecular Cancer
 [1];  [1];  [2];  [1];  [1];  [1];  [3];  [4];  [1]
  1. Shandong Univ., Jinan (China)
  2. The Fifth People's Hospital (China)
  3. Shandong Cancer and Hospital Inst. (China)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
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CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively. We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities. In conclusion, our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1257383
Journal Information:
Molecular Cancer, Vol. 13, Issue 1; ISSN 1476-4598
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 49 works
Citation information provided by
Web of Science

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Cited By (16)

HOXD9 promotes epithelial–mesenchymal transition and cancer metastasis by ZEB1 regulation in hepatocellular carcinoma journal October 2015
Lysine-specific demethylase 5C promotes hepatocellular carcinoma cell invasion through inhibition BMP7 expression journal October 2015
The cullin4A is up-regulated in chronic obstructive pulmonary disease patient and contributes to epithelial-mesenchymal transition in small airway epithelium journal May 2019
Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas journal March 2017
KDM6B promotes ovarian cancer cell migration and invasion by induced transforming growth factor‐β1 expression journal August 2018
Cul4A Modulates Invasion and Metastasis of Lung Cancer through Regulation of ANXA10 journal May 2019
CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition journal November 2015
Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells journal June 2015
MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression journal June 2016
Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3 journal February 2019
Recurrent Amplification at 13q34 Targets at CUL4A, IRS2, and TFDP1 As an Independent Adverse Prognosticator in Intrahepatic Cholangiocarcinoma journal December 2015
Cullin3 promotes breast cancer cells metastasis and epithelial-mesenchymal transition by targeting BRMS1 for degradation journal October 2015
The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications journal October 2015
Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway journal January 2016
CUL4A promotes proliferation and metastasis of colorectal cancer cells by regulating H3K4 trimethylation in epithelial–mesenchymal transition journal January 2017
Jumonji AT-rich interactive domain 1B overexpression is associated with the development and progression of glioma journal July 2016

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Related Subjects

60 APPLIED LIFE SCIENCES
Erlotinib
EGFR
Lung cancer
CUL4A