Deciphering the regulatory mechanism and clinical significance of ARID3B in stem-like properties of head-and-neck and colon cancers

• Main Authors: Tsai-Tsen Liao, 廖彩岑
• Other Authors: Muh-Hwa Yang
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/12728357660834725908

博士 === 國立陽明大學 === 臨床醫學研究所 === 105 === Let-7 is a crucial regulator for both stem cell differentiation and tumor repression. However, whether let-7 coordinates the gene expression beyond the direct targeting of regulated genes to generate a given phenotype is unclear. Here, we demonstrated a chromatin-dependent mechanism of let-7 that AT-rich interacting domain 3B (ARID3B) is the key regulator located at a higher hierarchical level to coordinate the expression of other core target genes of let-7. let-7 interferes ARID3B complex, including suppression of the expression of ARID3B and its interaction partner ARID3A and prevent ARID3B complex formation. The ARID3B complex recruits the histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and then promotes the transcription of embryonic specific stemness factors in head and neck cancer cells. In the head and neck cancer samples, let-7 levels are inversely associated with ARID3A and ARID3B levels and the accumulation of nuclear ARID3A and ARID3B correlates with and poorer prognosis. This result highlights the role of let-7 in regulating target genes through modifying their chromatin configuration. Further, we revealed that ARID3B regulated different targets in different cancer types and therefore increase the stem like properties of the cancer cells.Therefore, unraveling the mechanisms how cancer cells acquire the stem-like properties may allow clinicians to develop more approach to interfere with these processes and ultimately improve cancer treatment.