KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway

Lin Gao; Ru Zhao; Junmei Liu; Wenbo Zhang; Feifei Sun; Qianshuo Yin; Xin Wang; Meng Wang; Tingting Feng; Yiming Qin; Wenjie Cai; Qianni Li; Hanchen Dong; Xueqing Chen; Xueting Xiong; Hui Liu; Jing Hu; Weiwen Chen; Bo Han

doi:10.3389/fonc.2021.679173

KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway

Front Oncol. 2021 Nov 4:11:679173. doi: 10.3389/fonc.2021.679173. eCollection 2021.

Authors

Lin Gao¹, Ru Zhao¹, Junmei Liu², Wenbo Zhang¹, Feifei Sun¹, Qianshuo Yin³, Xin Wang¹, Meng Wang¹, Tingting Feng¹, Yiming Qin⁴, Wenjie Cai¹, Qianni Li¹, Hanchen Dong¹, Xueqing Chen¹, Xueting Xiong⁵, Hui Liu^{1

6}, Jing Hu^{1

6}, Weiwen Chen², Bo Han^{1

6}

Affiliations

¹ The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ School of Basic Medical Sciences, Shandong University, Jinan, China.
⁴ College of Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁶ Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Abstract

Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

Keywords: CRPC; Cdc42; EGFR; KIF15; protein stability.