Affiliation:
1. Department of Colorectal and Anal Surgery Shanghai Colorectal Cancer Research Center Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200092 China
2. Department of General Surgery State Key Laboratory of Genetic Engineering School of Life Sciences Zhongshan Hospital Fudan University Shanghai 200438 China
3. Center for Gastrointestinal Research Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center Baylor University Medical Center Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of Hope Comprehensive Cancer Center Duarte CA 91010 USA
Abstract
AbstractAlthough the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics‐ and proteomics‐based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome‐wide level in CRC. Serum‐induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4‐SP1/SP3 complex. Furthermore, targeting the ELK4‐SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9‐gene prognostic model based on the ELK4‐SP1/3 complex‐regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF‐independent manner, identifying the ELK4‐SP1/SP3 complex as a potential target for rational combination therapy.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)