Chen Yunyun, Zhang Kun, Zhang Rui, Wang Zhuo, Yang Liang, Zhao Tingting, Zhang Shihui, Lin Yong, Zhao Hongzhou, Liu Yongpan, Wei Yuxuan, Zhou Yijian, Zhang Jiaying, Ye Xianzong, Zhao Jing, Li Xinxin, Que Jianwen, Shi Songlin, Liu Kuancan
Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
Cell Death Discov. 2023 Oct 27;9(1):399. doi: 10.1038/s41420-023-01693-7.
Emerging evidence indicates that SOX2 is an oncogene for esophageal squamous cell carcinoma (ESCC). However, direct targeting of SOX2 is not feasible given that this transcription factor plays important roles in the maintenance of tissues such as the brain. Here, we identified CDP (Homeobox protein cut-like 1 or CASP) as a unique SOX2 binding partner enriched in ESCC with Duolink proximity ligation assay, bimolecular fluorescence complementation (BiFc) and immunoprecipitation. We then screened a peptide aptamer library using BiFc and immunoprecipitation and identified several peptide aptamers, including P58, that blocked the CDP/SOX2 interaction, leading to the inhibition of ESCC progress in vitro and in vivo. Upon administration, synthetic peptide P58, containing the YGRKKRRQRRR cell-penetrating peptide and the fluorophore TAMRA, also blocked the growth and metastasis of ESCC in both mice and zebrafish. Therefore, targeting the SOX2 binding partner CDP with peptide P58 offers an alternative avenue to treat ESCC with increased SOX2 levels.
新出现的证据表明，SOX2是食管鳞状细胞癌（ESCC）的一种致癌基因。然而，鉴于这种转录因子在维持诸如大脑等组织中发挥重要作用，直接靶向SOX2是不可行的。在这里，我们通过Duolink邻近连接分析、双分子荧光互补（BiFc）和免疫沉淀，鉴定出CDP（同源框蛋白类切割样1或CASP）是一种在ESCC中富集的独特SOX2结合伴侣。然后，我们使用BiFc和免疫沉淀筛选了一个肽适配体文库，并鉴定出几种肽适配体，包括P58，它们阻断了CDP/SOX2相互作用，导致ESCC在体外和体内的进展受到抑制。给药后，含有YGRKKRRQRRR细胞穿透肽和荧光团TAMRA的合成肽P58也阻断了ESCC在小鼠和斑马鱼中的生长和转移。因此，用肽P58靶向SOX2结合伴侣CDP为治疗SOX2水平升高的ESCC提供了一条替代途径。
