机构：[1]Central Laboratory, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Peking University School and Hospital of Stomatology, Beijing, China[2]Department of Stomatology, Beijing Tongren Hospital, Capital medical University, Beijing, China临床科室口腔科首都医科大学附属北京同仁医院首都医科大学附属同仁医院[3]Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China[4]Department of General Dentistry II, Peking University School and Hospital of Stomatology, Beijing, China[5]Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China[6]Shanxi Medical University School and Hospital of Stomatology, Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, China
The role of p53 deficiency or mutation in regulating nonhistone protein crotonylation and its impact on cancer development remain unclear. The present study identified crotonylation as a therapeutic target in patients with p53 deficiency or mutation in colorectal cancer. Crotonylome analysis revealed that p53 deficiency upregulated heterogeneous nuclear ribonucleoprotein C (HNRNPC) and HNRNPCK189Cr, promoting colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs through the MDM2/HDAC3 axis. Functional studies using HNRNPCK189Q (activating mutation) and HNRNPCK189R (inactivating mutation) confirmed the role of HNRNPCK189Cr in tumor growth. HDAC3 was identified as a specific decrotonylase of HNRNPCK189Cr. Sodium phytate, an HDAC3 agonist, effectively decrotonylated HNRNPCK189Cr and, in combination with HNRNPC siRNA, significantly inhibited the in vitro and in vivo growth of HCT116 p53-/- cells. An AOM/DSS-induced colorectal cancer model in K14-cre; p53 fl/fl mice validated the role of the p53/MDM2/HDAC3/HNRNPCK189Cr axis in tumor progression. Additionally, the findings in the oral cancer cells WSU-HN6 and non-small lung cancer cells H1299 were in line with those in the HCT116 cells, suggesting that the p53/MDM2/HDAC3/HNRNPCK189Cr regulatory mechanism plays a key role in a conserved manner. These findings revealed a novel mechanism by which p53 deficiency or mutation drives tumor progression via HNRNPCK189Cr through MDM2/HDAC3 axis-mediated CCND1 and MCM3 mRNA stability. Targeting HNRNPC and its crotonylation with sodium phytate and HNRNPC siRNA offers a promising therapeutic strategy, potentially converting p53 from an "undruggable" target to a "druggable" target.
基金：
National Natural Science Founda-tion of China [81970920, 81772873, 81771088]; Nature Science Foundation of Beijing Municipality, China [7232218]; Beijing Natural Science Foundation-Daxing Innovation Joint Fund Project, China [L246030]
第一作者机构：[1]Central Laboratory, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Peking University School and Hospital of Stomatology, Beijing, China
通讯作者：
通讯机构：[1]Central Laboratory, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Peking University School and Hospital of Stomatology, Beijing, China[3]Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
推荐引用方式(GB/T 7714)：
Sun Liangjie,Gao Xiaolei,Wang Meng,et al.Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs[J].CANCER LETTERS.2025,628:doi:10.1016/j.canlet.2025.217854.
APA：
Sun, Liangjie,Gao, Xiaolei,Wang, Meng,Zhang, Yixin,Sun, Ruiqing...&Wang, Yixiang.(2025).Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs.CANCER LETTERS,628,
MLA：
Sun, Liangjie,et al."Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs".CANCER LETTERS 628.(2025)
医学