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E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer

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Abstract

Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. Herein, we found the protein WNT5A, was significantly downregulated in BM tissues and EGFR-mutant samples. In addition, the overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared with the EGFR wide-type cells. We demonstrated a molecular mechanism whereby WNT5A be negatively regulated by transcription factor E2F1, and ERK1/2 inhibitor (U0126) suppressed E2F1’s regulation of WNT5A expression in EGFR-mutant cells. Furthermore, WNT5A inhibited β-catenin activity and the transcriptional levels of its downstream genes in cancer progression. Our research revealed the role of WNT5A in NSCLC BM with EGFR mutation, and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, supporting the notion that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFR-mutant NSCLC.

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Abbreviations

BM:

Brain metastasis

NSCLC:

Non-small cell lung cancer

EGFR:

Epidermal growth factor receptor

TKI:

Tyrosine kinase inhibitor

ERK1/2:

Extracellular signal-regulated kinase ½

WNT5A:

Wnt family member 5A

ROR2:

Receptor tyrosine kinase-like orphan receptor 2

β-Catenin:

Catenin beta 1

E2F1:

E2F transcription factor 1

PI3K:

Phosphoinositide 3-kinase

HDAC:

Histone deacetylase

cDNA:

Complementary DNA

qRT-PCR:

Quantitative real-time PCR

ChIP:

Chromatin immunoprecipitation

HR:

Hazard ratio

mut:

Mutation

wt:

Wild-type

GEO:

Gene Expression Omnibus

TFs:

Transcriptional factors

OS:

Overall survival

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Funding

This work was supported by the National Natural Science Foundation of China (81573090, 81172595, 81703165).

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Author notes

  1. Huanhuan Li, Fan Tong and Rui Meng are equal contributors.

Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China

    Huanhuan Li, Fan Tong, Rui Meng, Ling Peng, Jiaojiao Wang, Ruiguang Zhang & Xiaorong Dong

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  1. Huanhuan Li
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  2. Fan Tong
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Contributions

XRD conceived the study. HHL, LP, and JJW performed the experiments. HHL, FT, MR and RGZ analyzed the data. XRD and HHL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiaorong Dong.

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The authors declare no conflicts of interest.

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This study was approved by the Institutional Review Board of Huazhong University of Science and Technology. Written informed consent was obtained from all legal guardians of the patients. All animal experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals and were approved by the Committee on Animal Handling of Huazhong University of Science and Technology.

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Li, H., Tong, F., Meng, R. et al. E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer. Cell. Mol. Life Sci. 78, 2877–2891 (2021). https://doi.org/10.1007/s00018-020-03678-6

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