Knockout or inhibition of DHPS suppresses ovarian tumor growth and metastasis by attenuating the TGFβ pathway

Guannan Zhao; Xinxin Zhao; Ziping Liu; Baojin Wang; Peixin Dong; Hidemichi Watari; Lawrence M Pfeffer; Gabor Tigyi; Wenjing Zhang; Junming Yue

doi:10.1038/s41598-025-85466-5

Knockout or inhibition of DHPS suppresses ovarian tumor growth and metastasis by attenuating the TGFβ pathway

Sci Rep. 2025 Jan 6;15(1):917. doi: 10.1038/s41598-025-85466-5.

Authors

Guannan Zhao^{1

2}, Xinxin Zhao³, Ziping Liu³, Baojin Wang³, Peixin Dong⁴, Hidemichi Watari⁴, Lawrence M Pfeffer^{1

2}, Gabor Tigyi⁵, Wenjing Zhang⁶, Junming Yue^{7

8}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Collage of Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, United States.
² Center for Cancer Research, Collage of Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
³ Department of Obstetrics and Gynecology, The Third Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China.
⁴ Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan.
⁵ Department of Physiology, Collage of Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
⁶ Department of Genetics, Genomics & Informatics, Collage of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. [email protected].
⁷ Department of Pathology and Laboratory Medicine, Collage of Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, United States. [email protected].
⁸ Center for Cancer Research, Collage of Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, USA. [email protected].

Abstract

Deoxyhypusine synthase (DHPS) is an enzyme encoded by the DHPS gene, with high expression in various cancers, including ovarian cancer (OC). DHPS regulates the translation initiation factor EIF5A, and EIF5A2 knockout inhibits OC tumor growth and metastasis by blocking the epithelial-to-mesenchymal transition (EMT) and the TGFβ pathway. In this study, we show that DHPS is amplified in OC patients, and its elevated expression correlates with poor survival. Using lentiviral CRISPR/Cas9 vectors for DHPS knockout, we observed EMT inhibition in SKOV3 and OVCAR8 cells through suppressed hypusination and reduced EIF5A2 expression. Inhibition of DHPS activity with GC7 similarly blocked hypusination and EMT. Disrupting DHPS expression, either genetically or pharmacologically, inhibited primary tumor growth and metastasis in OC mouse models. These findings suggest that targeting DHPS and inhibiting hypusination could be promising strategies for OC treatment.

Keywords: DHPS; EIF5A; EMT; GC7; Hypusination; Metastasis; Orthotopic OC mouse models; Ovarian cancer; TGFβ.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Epithelial-Mesenchymal Transition* / genetics
Eukaryotic Translation Initiation Factor 5A
Female
Gene Expression Regulation, Neoplastic
Gene Knockout Techniques
Humans
Mice
Neoplasm Metastasis
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / metabolism
Ovarian Neoplasms* / pathology
Oxidoreductases Acting on CH-NH Group Donors* / antagonists & inhibitors
Oxidoreductases Acting on CH-NH Group Donors* / genetics
Oxidoreductases Acting on CH-NH Group Donors* / metabolism
Peptide Initiation Factors / genetics
Peptide Initiation Factors / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Signal Transduction*
Transforming Growth Factor beta* / metabolism

Substances

Transforming Growth Factor beta
deoxyhypusine synthase
RNA-Binding Proteins
Oxidoreductases Acting on CH-NH Group Donors
Eukaryotic Translation Initiation Factor 5A
Peptide Initiation Factors

Abstract

MeSH terms

Substances

Grants and funding