Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
School of Medicine and School of Life Sciences, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China.
Oncogene. 2018 Jun;37(26):3485-3500. doi: 10.1038/s41388-018-0161-z. Epub 2018 Mar 22.
Using whole genome sequencing, we identified gene amplification of CREPT in colorectal cancer (CRC). In this study, we aim to clarify its clinical significance, biological effects, and mechanism in CRC. CREPT was upregulated in CRC cell lines and in 47.37% (72/152) of primary CRC tumors. Amplification of CREPT was detected in 48.28% (56/116) of primary CRC tumors, which was positively correlated with its overexpression (P < 0.001). Multivariate analysis showed that CRC patients with CREPT protein overexpression were significantly associated with poor disease-free survival (P < 0.05). CREPT significantly accelerated CRC cell proliferation and metastasis both in vitro and in vivo. RNA-sequencing (seq) analysis uncovered that the tumor-promoting effect by CREPT was attributed to enhancing Wnt/β-catenin signaling. Using co-immunoprecipitation coupled with mass spectroscopy, we identified p300 protein was a novel CREPT interacting partner. CREPT greatly increased the interaction between p300 and β-catenin, thus promoting p300-mediated β-catenin acetylation and stabilization. Moreover, CREPT cooperated with p300, leading to elevated active histone acetylation markers H3K27ac and H4Ac and decreased repressive histone marker H3K9me3 at the promoters of Wnt downstream targets. In summary, CREPT plays a pivotal oncogenic role in colorectal carcinogenesis through promoting Wnt/β-catenin pathway via cooperating with p300. CREPT may serve as a prognostic biomarker of patients with CRC.
通过全基因组测序，我们在结直肠癌（CRC）中发现了 CREPT 的基因扩增。本研究旨在阐明其在 CRC 中的临床意义、生物学效应和机制。CREPT 在 CRC 细胞系和 47.37%（72/152）的原发性 CRC 肿瘤中上调。在 48.28%（56/116）的原发性 CRC 肿瘤中检测到 CREPT 的扩增，其与过表达呈正相关（P<0.001）。多变量分析表明，CRC 患者 CREPT 蛋白过表达与无病生存期差显著相关（P<0.05）。CREPT 显著加速了 CRC 细胞在体外和体内的增殖和转移。RNA-seq（seq）分析表明，CREPT 的促肿瘤作用归因于增强 Wnt/β-catenin 信号通路。通过免疫共沉淀结合质谱分析，我们鉴定出 p300 蛋白是 CREPT 的一种新型相互作用伙伴。CREPT 极大地增强了 p300 和 β-catenin 之间的相互作用，从而促进了 p300 介导的 β-catenin 乙酰化和稳定。此外，CREPT 与 p300 合作，导致 Wnt 下游靶基因启动子处的活性组蛋白乙酰化标记物 H3K27ac 和 H4Ac 升高和抑制性组蛋白标记物 H3K9me3 降低。总之，CREPT 通过与 p300 合作促进 Wnt/β-catenin 通路在结直肠癌发生中发挥关键致癌作用。CREPT 可能作为 CRC 患者的预后标志物。
