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RHBDL2 Drives Lipid Metabolic Reprogramming in Osteosarcoma via USP3-Mediated Deubiquitination of PPT1

ABSTRACT: Osteosarcoma (OS), a highly malignant bone tumor, is characterized by rapid progression and poor prognosis, with lipid metabolic reprogramming playing a crucial role in its pathogenesis. This study investigates the role of RHBDL2 in OS progression and its therapeutic potential. We demonstrate that RHBDL2 is overexpressed in OS tumor tissues, correlating with poor prognosis. RHBDL2 suppression significantly inhibits OS cell proliferation, migration, and lipid metabolism while enhancing apoptosis. Mechanistically, RHBDL2 interacts with USP3, enhancing its expression to stabilize PPT1 by removing ubiquitin chains, thereby promoting lipid synthesis and storage. Importantly, we identified Epigallocatechin gallate (EGCG) as a small-molecule inhibitor that disrupts the RHBDL2/USP3 interaction, potentially offering a therapeutic strategy to inhibit osteosarcoma progression without affecting physiological bone remodeling.

ORGANISM(S): Homo Sapiens

SUBMITTER: Kewei Zhu

PROVIDER: PXD062405 | iProX | Mon Mar 31 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Background: Osteosarcoma, a primary malignant bone tumor predominantly affecting children and adolescents, exhibits a dismal prognosis for patients with metastatic or recurrent disease, characterized by low five-year survival rates. This poor outcome is largely attributed to the incomplete understanding of the molecular mechanisms governing osteosarcoma aggressiveness and metastasis, coupled with a paucity of effective early diagnostic biomarkers and targeted therapeutic strategies. Consequently, elucidating the critical molecular events driving osteosarcoma pathogenesis and identifying novel biomarkers are of paramount importance for improving patient outcomes. Prior research has demonstrated aberrant expression of Zinc Finger DHHC-Type Palmitoyltransferase 9 (ZDHHC9) in various malignancies, but its specific function and clinical significance in osteosarcoma remain poorly defined. Methods: This study employed a comprehensive approach integrating bioinformatic analyses and experimental validation to investigate the functional role and clinical relevance of ZDHHC9 in osteosarcoma. Bioinformatic analyses (TIMER, GEPIA, TCGA databases) were utilized to examine ZDHHC9 expression across a pan-cancer landscape and its association with survival in osteosarcoma patients. Immunohistochemistry (IHC) and Western blotting were employed to analyze ZDHHC9 expression in clinical osteosarcoma specimens and cell lines. In vitro assays (CCK-8, colony formation, wound healing, Transwell, flow cytometry, and Western blotting) were performed to evaluate the impact of ZDHHC9 on osteosarcoma cell proliferation, migration, and invasion. Proteomic sequencing, molecular docking, and co-immunoprecipitation (Co-IP) experiments were conducted to explore the interaction between ZDHHC9 and KRAS. Western blotting was used to analyze the regulation of Raf1, ERK1/2, and p-ERK1/2 expression by ZDHHC9 and KRAS. Finally, a xenograft model was employed to assess the effect of ZDHHC9 on in vivo tumor growth. Results: Bioinformatic analyses revealed that elevated ZDHHC9 expression correlates with poor prognosis in osteosarcoma. IHC and Western blotting confirmed significantly increased ZDHHC9 expression in osteosarcoma tissues compared to adjacent non-tumorous tissues. Upregulation of ZDHHC9 was significantly associated with elevated Ki67 levels and advanced Enneking stage, suggesting a link to tumor aggressiveness. In vitro studies demonstrated that downregulation of ZDHHC9 suppressed osteosarcoma cell proliferation, migration, and invasion, while promoting apoptosis. Conversely, upregulation of ZDHHC9 elicited opposite effects. Proteomic sequencing revealed that ZDHHC9 knockdown significantly downregulated the expression of proteins associated with the RAS/MAPK signaling pathway. Functional experiments showed that overexpression of KRAS partially abrogated the inhibitory effects of ZDHHC9 knockdown on cell proliferation, migration, and invasion. Molecular docking and Co-IP experiments confirmed a specific interaction between ZDHHC9 and KRAS, leading to activation of the RAS/MAPK signaling pathway. Conclusion: ZDHHC9 promotes osteosarcoma cell proliferation, migration, and invasion by enhancing KRAS-mediated activity of the RAS/MAPK signaling pathway, which promotes cell cycle progression while inhibiting apoptosis.

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RHBDL2 Drives Lipid Metabolic Reprogramming in Osteosarcoma via USP3-Mediated Deubiquitination of PPT1

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