ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3‐Dependent Manner

Although 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 un...

Full description

Saved in:
Bibliographic Details
Published in:Advanced science 2023-11, Vol.10 (32), p.e2303378-e2303378
Main Authors: Zhu, Zhehui, Guo, Yuegui, Liu, Yun, Ding, Rui, Huang, Zhenyu, Yu, Wei, Cui, Long, Du, Peng, Goel, Ajay, Liu, Chen‐Ying
Format: Article
Language:English
Subjects:
Angiogenesis
Cell growth
Colorectal cancer
ELK4
Genes
Genomics
Growth factors
LRG1
Metastasis
Prostate cancer
SP1
SP3
Statistical analysis
Transcription factors
Tumorigenesis
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Although 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.
ISSN:2198-3844
2198-3844
DOI:10.1002/advs.202303378