FHIT suppresses cervical squamous cell carcinoma progression by negatively regulating UBE2I-mediated SUMO modification of NOTCH1
- Cell Signal. 2026 Sep:145:112582. doi: 10.1016/j.cellsig.2026.112582.
- 1. Department of Gynecology, Jinhua Maternal and Child Health Care Hospital, Jinhua 321000, Zhejiang, China.
- 2. Department of Dermatology, Jinhua Maternal and Child Health Care Hospital, Jinhua 321000, Zhejiang, China.
- 3. Lighthouse Research Institute, University of Nottingham Ningbo China, Ningbo 315000, Zhejiang, China.
- 4. Department of Laboratory, JinHua Municipal Central Hospital, Jinhua 321000, Zhejiang, China.
- 5. Department of Laboratory, JinHua Municipal Central Hospital, Jinhua 321000, Zhejiang, China. Electronic address: [email protected].
- 6. Department of Gynecology, Jinhua Maternal and Child Health Care Hospital, Jinhua 321000, Zhejiang, China. Electronic address: [email protected].
Purpose: FHIT functions as a tumor suppressor frequently silenced by promoter hypermethylation in multiple cancers, including cervical Cancer. This study elucidates its role in progression and immunoregulation of cervical squamous cell carcinoma (CSCC) and identifies downstream molecular mechanisms.
Methods: GEO datasets containing CSCC tissue data were mined to screen aberrantly expressed genes. TCGA database was queried to analyze FHIT expression and DNA methylation patterns between cervical Cancer and normal tissues; findings were validated by RT-qPCR, MSP-PCR and Western blot in CSCC versus normal cell lines. Gain- and loss-of-function experiments overexpressing or knocking down FHIT investigated its impact on proliferation, metastasis and macrophage modulation. Potential upstream regulators and pathway involvement were further explored.
Results: FHIT was predicted to be hypermethylated and downregulated in CSCC. Overexpression of FHIT in CSCC cells significantly suppressed cell proliferation, migration, and invasion. Furthermore, when co-cultured with macrophages, FHIT-overexpressing CSCC cells promoted the polarization of macrophages toward the anti-tumor M1 phenotype. Mechanistically, FHIT was found to bind to UBE2I protein and downregulate its expression. Overexpression of UBE2I reversed the tumor-suppressive effects of FHIT. UBE2I was shown to mediate SUMO modification at lysine residue K1607 of NOTCH1. Mutation at the K1607 site of NOTCH1 abolished the oncogenic effects induced by UBE2I in CSCC.
Conclusions: In summary, this study focuses on the antitumor role and molecular mechanisms of FHIT in CSCC. The FHIT/UBE2I/NOTCH1 regulatory axis may serve as a potential therapeutic target for CSCC through immunomodulatory strategies.