Cigliano, Antonio and Simile, Maria M. and Vidili, Gianpaolo and Pes, Giovanni M. and Dore, Maria P. and Urigo, Francesco and Cossu, Eleonora and Che, Li and Feo, Claudio and Steinmann, Sara M. and Ribback, Silvia and Pascale, Rosa M. and Evert, Matthias and Chen, Xin and Calvisi, Diego F. (2024) Fatty Acid Synthase Promotes Hepatocellular Carcinoma Growth via S-Phase Kinase-Associated Protein 2/p27<SUP>KIP1</SUP> Regulation. MEDICINA-LITHUANIA, 60 (7): 1160. ISSN 1010-660X, 1648-9144
Full text not available from this repository.Abstract
Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN's tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27(KIP1) in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27(KIP1) induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27(KIP1) non-phosphorylatable (p27(KIP1-T187A)) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27(KIP1) activators.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CELL-PROLIFERATION; POOR-PROGNOSIS; CANCER-CELLS; DEGRADATION; INHIBITOR; SKP2; LIPOGENESIS; EXPRESSION; P27(KIP1); APOPTOSIS; hepatocellular carcinoma; lipogenesis; FASN; SKP2; p27(KIP1); mouse models |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Jan 2026 10:30 |
| Last Modified: | 14 Jan 2026 10:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64954 |
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