PJA2 Suppresses Colorectal Cancer Progression by Controlling HDAC2 Degradation and Stability

作者：Zhihao Chen, Chaofan Peng, Chi Jin, Ye Wang, Tuo Wang, Peng Yang, Wen Peng, Qingyang Sun, Hengjie Xu, Hongxu Nie, Xiaowei Wang, Junwei Tang, Yueming Sun, Yifei Feng · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202401964 · 被引用次数：6 · 研究领域：Histone Deacetylase Inhibitors Research、Epigenetics and DNA Methylation、Protein Degradation and Inhibitors

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 progress...