ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner,Advanced Science

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ELK4 Promotes Colorectal Cancer Progression by Activating the Neoangiogenic Factor LRG1 in a Noncanonical SP1/3-Dependent Manner
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-02 , DOI: 10.1002/advs.202303378
Zhehui Zhu _{1,

2} , Yuegui Guo ₁ , Yun Liu ₁ , Rui Ding ₁ , Zhenyu Huang ₁ , Wei Yu ₂ , Long Cui ₁ , Peng Du ₁ , Ajay Goel ₃ , Chen-Ying Liu ₁

Affiliation

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.

中文翻译：

ELK4 通过非经典 SP1/3 依赖性方式激活新血管生成因子 LRG1 促进结直肠癌进展

尽管 MAPK/MEK/ERK 通路在结直肠癌 (CRC) 中普遍被激活，但 MEK/ERK 抑制剂在临床上的疗效有限。作为 MAPK 的下游靶标，ELK4 被认为主要通过与 SRF 形成复合物来发挥作用。ELK4是否可以作为潜在的治疗靶点尚不清楚，转录调控机制尚未得到系统分析。在此，表明 ELK4 促进 CRC 肿瘤发生。基于基因组学和蛋白质组学的综合方法确定了 SP1 和 SP3（而不是 SRF）作为 CRC 在全基因组水平上 ELK4 的合作功能伙伴。MAPK 血清诱导的 ELK4 磷酸化促进了其与 SP1/SP3 的相互作用。病理性新生血管生成因子 LRG1 被确定为 ELK4-SP1/SP3 复合物的直接靶标。此外，通过与 MEK/ERK 抑制剂和相对特异性的 SP1 抑制剂光神霉素 A (MMA) 联合治疗，靶向 ELK4-SP1/SP3 复合物，对 CRC 产生协同抗肿瘤作用。临床上，ELK4是CRC预后不良的标志物。基于 ELK4-SP1/3 复合体调控基因集的 9 基因预后模型显示出稳健的预后准确性。结果表明，ELK4与SP1和SP3协同转录调节LRG1，以不依赖SRF的方式促进CRC肿瘤发生，从而确定ELK4-SP1/SP3复合物作为合理联合治疗的潜在靶点。

更新日期：2023-10-02

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