NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2

Donglin Ding; Huixing Huang; Quanfu Li; Wenbo Yu; Chenji Wang; Haijie Ma; Jiaxue Wu; Yongjun Dang; Long Yu; Wei Jiang

doi:10.1038/s41420-020-0236-9

NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2

Cell Death Discov. 2020 Jan 22:6:3. doi: 10.1038/s41420-020-0236-9. eCollection 2020.

Authors

Donglin Ding^#^{1

2

3}, Huixing Huang^#^{1

2}, Quanfu Li^#¹, Wenbo Yu², Chenji Wang², Haijie Ma⁴, Jiaxue Wu², Yongjun Dang¹, Long Yu², Wei Jiang¹

Affiliations

¹ 1Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² 2State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China.
³ 3Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN USA.
⁴ 4Laboratory of Cytobiology and Molecular Biology, The Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, Zhejiang China.

^# Contributed equally.

Abstract

Nuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.

Keywords: Diagnostic markers; Hepatocellular carcinoma; Prognostic markers; Tumour biomarkers.