Dataset Information

PAD4-dependent citrullination of nuclear translocation of GSK3β promotes colorectal cancer progression via the degradation of nuclear CDKN1A.

ABSTRACT: Peptidylarginine deiminase 4 (PAD4), a Ca²⁺-dependent enzyme, catalyzes the conversion of arginine to citrulline and has been strongly associated with many malignant tumors. However, the molecular mechanisms of PAD4 in the development and progression of colorectal cancer (CRC) remain unclearly defined. In our study, PAD4 expression was increased in CRC tissues and cells, and was closely related to tumor size, lymph node metastasis. Moreover, the transcription factor KLF9 directly bound to PADI4 gene promoter, leading to overexpression of PAD4 in CRC cells, which augmented cell growth and migration. We revealed that PAD4 interacted with and citrullinated glycogen synthase kinase-3β (GSK3β) in CRC cells, and GSK3β Arg-344 was the dominating PAD4-citrullination site. Furthermore, IgL2 and catalytic domains of PAD4 directly bound to the kinase domain of GSK3β in CRC cells. Mechanistically, PAD4 promoted the transport of GSK3β from the cytoplasm to the nucleus, thereby increasing the ubiquitin-dependent proteasome degradation of nuclear cyclin-dependent kinase inhibitor 1 (CDKN1A). Our study is the first to reveal the details of a critical PAD4/GSK3β/CDKN1A signaling axis for CRC progression, and provides evidence that PAD4 is a potential diagnosis biomarker and therapeutic target in CRC.

SUBMITTER: Luo X

PROVIDER: S-EPMC9483803 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PAD4-dependent citrullination of nuclear translocation of GSK3β promotes colorectal cancer progression via the degradation of nuclear CDKN1A.

Luo Xiaonuan X Chang Shanshan S Xiao Siyu S Peng Yin Y Gao Yuli Y Hu Fan F Liang Jianxue J Xu Yidan Y Du Kaining K Chen Yang Y Qin Jiequan J Meltzer Stephen J SJ Deng Shiqi S Feng Xianling X Fan Xinmin X Hou Gangqiang G Jin Zhe Z Zhang Xiaojing X

Neoplasia (New York, N.Y.) 20220913

Peptidylarginine deiminase 4 (PAD4), a Ca<sup>2+</sup>-dependent enzyme, catalyzes the conversion of arginine to citrulline and has been strongly associated with many malignant tumors. However, the molecular mechanisms of PAD4 in the development and progression of colorectal cancer (CRC) remain unclearly defined. In our study, PAD4 expression was increased in CRC tissues and cells, and was closely related to tumor size, lymph node metastasis. Moreover, the transcription factor KLF9 directly boun ...[more]

PMID: 36113195

Similar Datasets

Project description:BackgroundNuclear-cytoplasmic transport proteins (NCTPs) impact the transport of proteins and RNA molecules between the nucleus and cytoplasm in tumor cells, making them promising targets for cancer therapy. Currently, the molecular mechanism and function of Nuclear RNA export factor 3 (NXF3) in gastric cancer (GC) remains unclear.MethodsWe used Univariate Cox regression analysis and LASSO regression analysis, Receiver Operating Characteristic (ROC) curves to construct and evaluate a NCTP prognosis risk scoring model (NCTP model). Moreover, we identified the key NCTP (NXF3) affecting GC through differential expression and prognosis analysis. Subsequently, we introduced NXF3 shRNA into GC cells to investigate the impact of NXF3 on the cell proliferation, cell migration, invasion, and cell cycle and apoptosis and tumor growth by CCK-8 assay, transwell, wound healing assay, Flow cytometry, and nude mice subcutaneous tumor in vitro and in vivo. Furthermore, we investigated the key molecules influenced by NXF3 through piRNA-Seq, RNA-Seq, RIP-Seq, IP-MS, and Nuclear-cytoplasmic transcriptomics.ResultsWe constructed a prognostic risk model related to 3 NCTPs, including NXF3, GLE1 and RANGAP. The NCTP model effectively predicts the prognosis of GC patients. The low-risk group exhibited a significantly higher overall survival rate than that of the high-risk group. Notably, NXF3 is identified as a crucial NCTP in GC, and its high expression is associated with poor prognosis of GC patients. Knocking down of NXF3 significantly inhibited the proliferation, invasion, migration, cell cycle, tumor growth and induced cell apoptosis of GC cells in vitro and in vivo. Mechanistically, NXF3 modulates the cell cycle, cellular senescence related oncogenic pathways via piRNA-target network. Specifically, our findings highlighted several piRNA-related signaling pathways in GC, such as piRNA_3457319-CCND1/CDKN1A-p53, piRNA_2847077-TGFB3/TGFBR2-Cellular senescence, piRNA_448895-IGF1/PDGFRA/ACTB/MAP2K6-Rap1. Moreover, NXF3 was shown to facilitate the nuclear export of CDK5RAP3 mRNA, thereby promoting cell cycle progression and increasing cancer cell proliferation in gastric cancer.ConclusionOur study demonstrates that NXF3 modulates cell cycle progression and promotes gastric cancer development through piRNA-related pathways and the nuclear export of CDK5RAP3 mRNA. Targeting NXF3 represents a promising strategy for developing novel therapeutic approaches for gastric cancer.

Dataset Information

PAD4-dependent citrullination of nuclear translocation of GSK3β promotes colorectal cancer progression via the degradation of nuclear CDKN1A.

Publications

PAD4-dependent citrullination of nuclear translocation of GSK3β promotes colorectal cancer progression via the degradation of nuclear CDKN1A.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets