The interplay between TEAD4 and KLF5 promotes breast cancer partially through inhibiting the transcription of <i>p27</i>Kip1

Abstract

// Chunyan Wang 1, 2, 3, * , Zhi Nie 3, * , Zhongmei Zhou 1 , Hailin Zhang 1 , Rong Liu 1 , Jing Wu 1, 2, 4 , Junying Qin 1, 2 , Yun Ma 3 , Liang Chen 3 , Shumo Li 3 , Wenlin Chen 5 , Fubing Li 1, 2 , Peiguo Shi 1, 2 , Yingying Wu 3 , Jian Shen 3 , Ceshi Chen 1 1 Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China 2 University of The Chinese Academy of Sciences, Beijing, China 3 First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China 4 Department of Biochemistry, Kunming Medical University, Kunming, Yunnan, China 5 Cancer Hospital, Kunming Medical University, Kunming, Yunnan, China * These authors have contributed equally to this work Correspondence to: Ceshi Chen, e-mail: chenc@mail.kiz.ac.cn Keywords: TEAD4, KLF5, p27, hippo pathway, TNBC Received: January 10, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: April 10, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: April 22, 2015 ABSTRACT Growing evidence suggests that YAP/TAZ are mediators of the Hippo pathway and promote breast cancer. However, the roles of YAP/TAZ transcription factor partners TEADs in breast cancer remain unclear. Here we found that TEAD4 was expressed in breast cancer cell lines, especially in triple negative breast cancers (TNBC) cell lines. TEAD4 binds to KLF5. Knockdown of either TEAD4 or KLF5 in HCC1937 and HCC1806 cells induced the expression of CDK inhibitor p27 . Depletion of either TEAD4 or KLF5 activated the p27 gene promoter and increased the p27 mRNA levels. Depletion of p27 partially prevents growth inhibition caused by TEAD4 and KLF5 knockdown. TEAD4 overexpression stimulated proliferation in vitro and tumor growth in mice, while stable knockdown of TEAD4 inhibited proliferation in vitro and tumor growth in mice. Thus TEAD4 and KLF5, in collaboration, promoted TNBC cell proliferation and tumor growth in part by inhibiting p27 gene transcription. TEAD4 is a potential target and biomarker for the development of novel therapeutics for breast cancer.