Genome-wide maps of chromatin binding of FOXD3

The tumor-initiating cells (TIC) are cell population that can initiate tumor, mediate drug resistance, and give rise to metastasis. FOXD3 is a forkhead box (Fox) transcription factor family that regulates the pluripotency of embryonic stem cell and tumorigenicity. However, it is unclear whether FOXD3 play any role in TIC and tumor metastasis. Here, we report that FOXD3 is down-regulated in tumor initiating cells and negatively correlated with higher histologic grades and positive lymph node metastasis. FOXD3 repress TIC expansion, cell migration, drug resistance and osteogenesis in vitro and in vivo. Mechanically, we found that FOXD3 repress a cohort of genes including SET and WDR5 and to regulate several TIC related signaling pathway. Moreover, SET and WDR5 was positively correlated with the CSC abundance and tumor progression. Besides, patients with high expression of SET and WDR5 presented a poorer overall survival. Collectively, our work defined that FOXD3-WDR5-SET axis that repress TIC accumulation and lung cancer progression.