Chen Zhihao, Peng Chaofan, Jin Chi, Wang Ye, Wang Tuo, Yang Peng, Peng Wen, Sun Qingyang, Xu Hengjie, Nie Hongxu, Wang Xiaowei, Tang Junwei, Sun Yueming, Feng Yifei
Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P. R. China.
Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, P. R. China.
Adv Sci (Weinh). 2025 Apr;12(13):e2401964. doi: 10.1002/advs.202401964. Epub 2025 Feb 10.
PJA2 is documented to degrade various substrates. Nevertheless, the role of PJA2 as an E3 ubiquitin-protein ligase in colorectal cancer (CRC) progression remains unexplored. The correlation between PJA2 mRNA levels and clinical characteristics is investigated using data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) are utilized to evaluate PJA2 expression levels in CRC tissues. The biological functions of PJA2 are confirmed through colony formation assays and azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model of CRC, among other experimental approaches. The underlying molecular mechanisms of PJA2 action are elucidated using RNA sequencing (RNA-seq), co-immunoprecipitation (co-IP), proximity ligation assay (PLA), and chromatin immunoprecipitation (ChIP). Our research discovered that PJA2 is downregulated in CRC tissues and decreased PJA2 expression correlates with poor prognosis. Functionally, in vivo and in vitro experiments uncovered that PJA2 inhibits tumor cell proliferation and promotes apoptosis. Mechanistically, PJA2 recognized histone deacetylase 2 (HDAC2) via its RING-B-box domain (RBD) and bind to the N-terminal of HDAC2, facilitating ubiquitination at the lysine 90 (K90) residue. PJA2-mediated degradation of HDAC2 counteracts the transcriptional repression of the interferon-induced protein with the tetratricopeptide repeats (IFIT) family, thereby suppressing CRC progression. The data demonstrates that PJA2 suppresses CRC progression through the PJA2/HDAC2/IFIT axis, and its expression is regulated by HDAC2, thus constituting a positive feedback loop. Consequently, PJA2 may serve as a potential therapeutic target for CRC, and interrupting this feedback loop can represent a viable treatment strategy to restrain CRC progression.
已有文献记载PJA2可降解多种底物。然而，PJA2作为E3泛素蛋白连接酶在结直肠癌（CRC）进展中的作用仍未得到探索。利用来自癌症基因组图谱（TCGA）数据库的数据研究了PJA2 mRNA水平与临床特征之间的相关性。采用定量实时聚合酶链反应（qRT-PCR）和免疫组织化学（IHC）来评估CRC组织中PJA2的表达水平。通过集落形成试验和CRC的氧化偶氮甲烷/硫酸葡聚糖钠（AOM/DSS）小鼠模型等实验方法证实了PJA2的生物学功能。使用RNA测序（RNA-seq）、免疫共沉淀（co-IP）、邻近连接分析（PLA）和染色质免疫沉淀（ChIP）阐明了PJA2作用的潜在分子机制。我们的研究发现，PJA2在CRC组织中表达下调，且PJA2表达降低与预后不良相关。在功能上，体内和体外实验发现PJA2抑制肿瘤细胞增殖并促进细胞凋亡。从机制上讲，PJA2通过其RING-B-box结构域（RBD）识别组蛋白去乙酰化酶2（HDAC2）并与HDAC2的N端结合，促进赖氨酸90（K90）残基的泛素化。PJA2介导的HDAC2降解抵消了具有四肽重复序列的干扰素诱导蛋白（IFIT）家族的转录抑制作用，从而抑制CRC进展。数据表明，PJA2通过PJA2/HDAC2/IFIT轴抑制CRC进展，其表达受HDAC2调节，从而构成一个正反馈环。因此，PJA2可能作为CRC的潜在治疗靶点，中断这个反馈环可能代表一种抑制CRC进展的可行治疗策略。
