SETDB2 promoted breast cancer stem cell maintenance by interaction with and stabilization of ΔNp63α protein
Liu Ying, Fei Xie, Jialun Li, Xiao Jianpeng, Jie Wang, Mei Zhaolin, Fan Hongjia, Huan Fang, Sha Li, Wu Qiuju, Lin Yuan, Liu Cuicui, You Peng, Zhao Weiwei, Wang Lulu, Wong Jiemin, Jing Li, Feng Jing
Abstract
The histone H3K9 methyltransferase SETDB2 is involved in cell cycle dysregulation in acute leukemia and has oncogenic roles in gastric cancer. In our study, we found that SETDB2 plays essential roles in breast cancer stem cell maintenance. Depleted SETDB2 significantly decreased the breast cancer stem cell population and mammosphere formation in vitro and also inhibited breast tumor initiation and growth in vivo. Restoring SETDB2 expression rescued the defect in breast cancer stem cell maintenance. A mechanistic analysis showed that SETDB2 upregulated the transcription of the Np63 downstream Hedgehog pathway gene. SETDB2 also interacted with and methylated Np63, and stabilized Np63 protein. Restoring Np63 expression rescued the breast cancer stem cell maintenance defect which mediated by SETDB2 knockdown. In conclusion, our study reveals a novel function of SETDB2 in cancer stem cell maintenance in breast cancer.