Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells
Hao Wang, Zhenzhen Lin, Zhe Nian, Wei Zhang, Wenxu Liu, Fei Yan, Zengtuan Xiao, Xia Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu
Hao Wang, Zhenzhen Lin, Zhe Nian, Wei Zhang, Wenxu Liu, Fei Yan, Zengtuan Xiao, Xia Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu
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Research Article Cell biology Oncology

Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells

Abstract

The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. In this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives the transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung-infiltrating tumor cells in xenograft models and predicted poor prognosis of patients with lung cancer. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured the chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this led to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of patients with GFI1-positive lung cancer.

Authors

Hao Wang, Zhenzhen Lin, Zhe Nian, Wei Zhang, Wenxu Liu, Fei Yan, Zengtuan Xiao, Xia Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu

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Figure 1

GFI1 is expressed in lung cancer cells and predicts poor prognosis.

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GFI1 is expressed in lung cancer cells and predicts poor prognosis. (A) ...
(A) Transcription factor binding motif enrichment in 29 human SCLC lines versus 118 NSCLC lines generated by Minna et al. (B) GFI1 expression in various lung cell types were screened in the Minna et al. study’s transcriptional profiles. GFI1 expression was significantly higher in SCLCs than in NSCLCs and was enhanced in both groups compared with normal epithelium. (C) RT-PCR and immunoblot of GFI1 expression in the indicated cell lines. See complete unedited blots in the supplemental material. (D) IHC staining with anti-GFI1 antibody was performed on 10 normal lung tissues adjacent to tumors and 242 NSCLC and 37 SCLC specimens. Scale bars: 20 μm. The frequency of samples with no (0), low (0.1–3.9), or high (4.0–8.0) GFI1 staining stratified by IHC-defined lung cancer subtype. (E) High GFI1 expression level correlated with stage III disease in NSCLC. (F) High GFI1 expression level correlated with distant lymph node metastasis in NSCLC. (G) Kaplan-Meier survival rates for 96 patients with stage I–II NSCLC disease with low versus high GFI1 expression were compared. Median value of GFI1 expression was used as the cutoff. (H) Kaplan-Meier survival rates for 51 patients with stage III NSCLC disease with low versus high GFI1 expression were compared. Median value of GFI1 expression was used as the cutoff.