FOXA1 reprograms the TGF-β-stimulated transcriptional program from a metastasis promoter to a tumor suppressor in nasopharyngeal carcinoma.

Abstract

Nasopharyngeal carcinoma (NPC) is a unique subtype of head and neck squamous carcinoma that is notorious for its high metastatic potential. In this study, we reported that FOXA1 protein was decreased in NPC cells. Loss of FOXA1 is associated with lymph node metastasis and poor prognosis. Silencing FOXA1 in NP69 and C666-1 NPC cells accelerated cell proliferation and migration, while re-expression of FOXA1 has opposite effects. Microarray and RNA-seq analysis revealed that re-expression of FOXA1 in NPC cells reprogrammed the TGF-β-stimulated transcription program, which is characterized by promotion of TGF-β-inducible tumor-suppressive targets but repression of TGF-β-inducible oncogenes expression in NPC cells, leading to restoration of NPC cell sensitivity to TGF-β's growth-inhibitory effect. BAMBI, a TGF-β responsive tumor suppressor, was induced by FOXA1 in NPC cells. FOXA1 binding on the BAMBI gene facilitated SMAD2/3 binding to the BAMBI promoter via increasing BAMBI associated H3K4me1 and H3K27ac modification. Enforced expression of BAMBI in NPC cells suppressed cell proliferation and invasiveness. Our data suggested that FOXA1 is a master factor in controlling the TGF-β-stimulated transcriptome and a regulator of TGF-β biological functions in NPC oncogenesis.

• Authors: Junjun Li, Wei Wang, Shengnan Chen, Jing Cai, Yuanyuan Ban, Qian Peng, Yin Zhou, Zhaoyang Zeng, Xiaoling Li, Wei Xiong, Guiyuan Li, Mei Yi, Bo Xiang
• Journal: Cancer letters (Cancer Lett) Vol. 442 Pg. 1-14 (02 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30392786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• BAMBI protein, human
• FOXA1 protein, human
• Hepatocyte Nuclear Factor 3-alpha
• Histones
• Membrane Proteins
• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta

Topics

• Acetylation
• Animals
• Binding Sites
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cellular Reprogramming
• Gene Expression Regulation, Neoplastic
• Hepatocyte Nuclear Factor 3-alpha (genetics, metabolism)
• Histones (metabolism)
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Nasopharyngeal Carcinoma (genetics, metabolism, secondary)
• Nasopharyngeal Neoplasms (genetics, metabolism, pathology)
• Neoplasm Invasiveness
• Promoter Regions, Genetic
• Signal Transduction
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transcriptional Activation
• Transforming Growth Factor beta (metabolism)
• Xenograft Model Antitumor Assays