Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in ESCC patients. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improves radiosensitivity in both nude mice and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α-RSK4-GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
Mingyang Li, Linni Fan, Donghui Han, Zhou Yu, Jing Ma, Yixiong Liu, Peifeng Li, Danhui Zhao, Jia Chai, Lei Jiang, Shiliang Li, Juanjuan Xiao, Qiuhong Duan, Jing Ye, Mei Shi, Yongzhan Nie, Kai-Chun Wu, Dezhong Joshua Liao, Yu Shi, Yan Wang, Qingguo Yan, Shuangping Guo, Xiu-Wu Bian, Feng Zhu, Jian Zhang, Zhe Wang