PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.

Abstract

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

• Authors: Chen-Hui Cao, Han Ling, Kai Han, Xiao-Peng Lu, Mu-Yan Cai, Jing-Hua Cao, Jie Zhou, Zhi-Cheng Xiang, Jie-Wei Chen, Si Li, Jin-Long Lin, Jin-Ling Duan, Jie Luo, Yu-Jing Fang, Zhi-Zhong Pan, Li Liang, Feng Wang, Dan Xie, Feng-Wei Wang
• Journal: Oncogene (Oncogene) Vol. 40 Issue 49 Pg. 6680-6691 (12 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34645979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Biomarkers, Tumor
• Phosphotransferases (Phosphate Group Acceptor)
• PPIP5K2 protein, human

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• DNA Damage
• DNA Repair
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Phosphotransferases (Phosphate Group Acceptor) (genetics, metabolism)
• Prognosis
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays