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

Jie Cheng1,2,*, Wenxin Li1,*, Bo Kang1,*, Yanwen Zhou1,*, Jiasheng Song3, Songsong Dan1, Ying Yang1, Xiaoqian Zhang1, Jingchao Li2, Shengyong Yin1,4, Hongcui Cao1, Hangping Yao1, Chenggang Zhu2, Wen Yi1,2, Qingwei Zhao1,5, Xiaowei Xu6, Min Zheng1, Shusen Zheng1,4, Lanjuan Li1, Binghui Shen7 & Ying-Jie Wang1

Nat Commun. 2015 Jun 10;6:7209. doi: 10.1038

Speaker: Ko-Lun Yen (顏克倫)                            Time: 14:00~15:00, Oct, 28, 2015

Commentator: Ai-Li Shiau (蕭璦莉 教授)         Place: Room 601

Abstract：

    Oct4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is involved essentially in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct4 expression must be closely regulated; too much or too little can cause differentiation of the cells. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that originally characterized as a key factor responding to environmental toxicants. However, recent studies indicated that AhR has oncogenic and tumor-suppressive activities, depending on specific ligand that distinctly binds to its promiscuous ligand-binding pocket^[1]. Since the increasing attention for its critical roles in embryogenesis and tumorigenesis, the potential roles of the AhR and its synthetic ligand in stem cell and cancer stem cell biology gradually  to be appreciated. For instance, retinoic acid (RA)-induced differentiation of leukemia cells correlated with increased levels of AhR and decreased levels of Oct4. However, it remains unknown whether any natural or endogenously produced AhR ligands can control the expression of Oct4 in normal stem cells or stem-like cancer cells, and what the underlying mechanism might be. The results show that the Oct4 expression can be elevated by reducing the endogenous ITE levels in cancer cells, 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 tumor models. Here, the results further reveal a role of tryptophan derivatives and the AhR signaling pathway in regulating cancer cell stemness and open a new therapeutic avenue to target stem-like cancer cells.

Reference：

1.     Feng, S., Cao, Z. & Wang, X. Role of aryl hydrocarbon receptor in cancer. Biochim. Biophys. Acta 1836, 197-210 (2013).

2.     Bunaciu, R. P. & Yen, A. Activation of the aryl hydorcarbon receptor AhR promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4. Cancer Res. 71, 2371-2380 (2011)