FOXA1 reprograms the TGF-β-stimulated transcriptional program from a metastasis promoter to a tumor suppressor in nasopharyngeal carcinoma. (1st February 2019)

• Record Type: Journal Article
• Authors: Li, Junjun; Wang, Wei; Chen, Shengnan; Cai, Jing; Ban, Yuanyuan; Peng, Qian; Zhou, Yin; Zeng, Zhaoyang; Li, Xiaoling; Xiong, Wei; Li, Guiyuan; Yi, Mei; Xiang, Bo
• Is Part Of: Cancer letters. Volume 442(2019)
• Page Start: 1
• Page End: 14
• Publication Date: 2019-02-01
• Subjects: TGF-β/SMAD signaling -- FOXA1 -- Nasopharyngeal carcinoma -- BAMBI; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.10.036
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: We reported the first time that loss of FOXA1 predicts unfavorable prognosis in NPC. FOXA1 is a bona fide tumor suppressor gene in NPC development. FOXA1 reprograms TGF-β-stimulated transcription from a metastasis promotive to a growth suppressive program. FOXA1 cooperates with TGF-β activated SMAD complex to upregulate BAMBI expression in NPC cells.