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

Abstract

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.

The disruptive role of LRG1 on the vasculature and perivascular microenvironment

“…These include IL-6, IL-1β, TNF-α, IL-17, IL-4, IL-10 and IL-33 and they may act either alone or synergistically (36,(64)(65)(66)(67)(68). In addition, PPARβ/δ is able to bind the LRG1 promoter to activate transcription as reported in a chromatin immunoprecipitation assay (47), and similarly, both ELK1 and ELK4 transcription factors have been shown to initiate LRG1 transcription upon mechanical strain (41) and through cooperation with Sp1/Sp3 complex (69), respectively. FOS-like 1 was also identified as a novel activator of LRG1 in a transcriptomics study (39).…”

“…HIF-1α knockdown was shown to block LRG1-mediated angiogenesis, EMT, and tumor invasiveness, and is consistent with LRG1 being induced in response to hypoxia ( 84 ). In another study, ERK mediated phosphorylation of ELK4 in a human colorectal cell line resulted in complex formation with SP1/3 and the induction of LRG1 gene expression ( 69 ). This, it was argued, results in enhanced tumor angiogenesis through activation of the TGF-β-SMAD1/5 pathway in endothelial cells.…”