Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells.

Jie Cheng,Chenggang Zhu,Wen Yi,Binghui Shen,Jingchao Li,Xiaowei Xu,Shusen Zheng,Lanjuan Li,Shengyong Yin,Ying Yang,Wenxin Li,Xiaoqian Zhang,Bo Kang,Songsong Dan,Min Zheng,Jingkuan Song ,Cao H ,Hang Yao ,Yi Zhou ,Qiu Zhao ,Yingjie Wang

doi:10.1038/ncomms8209

Abstract

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis. Here we show that a variety of tryptophan derivatives that act as endogenous AhR ligands can affect the transcription level of the master pluripotency factor Oct4. Among them, ITE enhances the binding of the AhR to the promoter of Oct4 and suppresses its transcription. Reduction of endogenous ITE levels in cancer cells by tryptophan deprivation or hypoxia leads to Oct4 elevation, which can be reverted by administration with synthetic ITE. Consequently, synthetic ITE induces the differentiation of stem-like cancer cells and reduces their tumorigenic potential in both subcutaneous and orthotopic xenograft tumour models. Thus, our results reveal a role of tryptophan derivatives and the AhR signalling pathway in regulating cancer cell stemness and open a new therapeutic avenue to target stem-like cancer cells.

Highlights

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis
To explore the potential correlation between AhR and Oct[4] expression, we compared their mRNA levels in two human pluripotent stem cell lines (embryonic stem cell (ESC) H1, embryonal carcinoma cell (ECC) NCCIT), five human cancer cell lines (HeLa, HepG2, U87, HT-29 and MCF-7) and three human non-tumour cell lines (HUVEC, LO2 and 293T; Fig. 1a)
Among various normal human tissues, placenta derived from the Oct4deficient trophectoderm exhibited the highest level of AHR mRNA, in general there was a positive correlation between the POU5F1 and AHR mRNA levels (Supplementary Fig. 4)

Summary

Introduction

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor originally identified and characterized as a key factor responding to environmental toxicants, is gaining increasing attention for its critical roles in immune responses[1,2] and carcinogenesis[3,4]. It has either oncogenic or tumour-suppressive activities, depending on each specific ligand that can distinctly bind to its promiscuous ligand-binding pocket[3,4,5]. Synthetic ITE induced the differentiation of stemlike cancer cells and reduced their tumorigenic potential in mouse xenograft tumour models

Methods

Results

Conclusion