STAT3/HOTAIR Signaling Axis Regulates HNSCC Growth in an EZH2-dependent Manner

• Published in: Clinical cancer research 2018-06, Vol.24 (11), p.2665-2677
• Main Authors: Sun, Shanshan, Wu, Yansheng, Guo, Wenyu, Yu, Feng, Kong, Lingping, Ren, Yu, Wang, Yu, Yao, Xiaofeng, Jing, Chao, Zhang, Chao, Liu, Mingyang, Zhang, Yuqing, Zhao, Minghui, Li, Zhaoqing, Wu, Chuanqiang, Qiao, Yu, Yang, Jingxuan, Wang, Xudong, Zhang, Lun, Li, Min, Zhou, Xuan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; AKT protein; Animals; Antineoplastic Agents - pharmacology; Antisense RNA; Cancer; Cell Cycle - genetics; Cell Line, Tumor; Cell Proliferation; Cisplatin; Correlation analysis; Disease Models, Animal; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein - metabolism; Epidermal growth factor receptors; Epithelium; Experimental design; Gene Expression Regulation, Neoplastic; Head; Head & neck cancer; Humans; Mice; Monoclonal antibodies; Platinum; Ribonucleic acid; RNA; RNA Interference; RNA, Long Noncoding - genetics; RNA, Small Interfering - genetics; Sensitivity; Signal Transduction; Signaling; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Stat3 protein; STAT3 Transcription Factor - metabolism; Targeted cancer therapy; Transcription; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-2248

PI3K and STAT3 are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate head and neck squamous cell cancer (HNSCC) growth. The lncRNA HOX transcript antisense RNA ( ) was found to modulate the progression of HNSCC. In this study, we attempted to establish the correlation of PI3K/STAT3/HOTAIR signaling with the progression of HNSCC and its sensitivity toward platinum-based and targeted anti-EGFR combination therapy. We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by assays. HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC. .