Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:37821935", "kind": "science-record", "revision": 2, "content_hash": "sha256:afadeffb48ca8f52561959cd0876ca334899826fe77230f44c8465d0bec022a6", "created_at": "2026-11-01T19:02:41Z", "updated_at": "2026-11-01T21:31:43Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation.", "doi": "10.1186/s13046-023-02842-7", "pmid": "37821935", "authors": ["Yananlan Chen", "Xiao Xu", "Yirui Wang", "Yaodong Zhang", "Tao Zhou", "Wangjie Jiang", "Ziyi Wang", "Jiang Chang", "Shuochen Liu", "Ruixiang Chen", "Jijun Shan", "Jifei Wang", "Yuming Wang", "Changxian Li", "Xiangcheng Li"], "journal": "Journal of experimental & clinical cancer research : CR", "year": 2023, "abstract": "BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear.\nMETHODS: Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia.\nRESULTS: SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery.\nCONCLUSION: Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.", "claims": [{"id": "claim-method", "statement": "The Kaplan‒Meier method and the log-rank test were applied to estimate overall survival (OS) and disease-free survival (DFS). A Cox proportional hazard regression model was used for multivariate analysis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:37821935", "locator": "sections[6] \"Statistical analysis\" paragraph 2", "quote": "The Kaplan‒Meier method and the log-rank test were applied to estimate overall survival (OS) and disease-free survival (DFS). 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METHODS: Next-generation sequencing (NGS) was performed with paired CCA tissues", "nclear. METHODS: Next-generation sequencing (NGS) was performed with paired CCA tissues and n", "r hypoxia. RESULTS: SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associ"], "order_basis": "paper_text_order:545", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["asets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression"], "order_basis": "paper_text_order:847", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of", "issues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructe"], "order_basis": "paper_text_order:980", "id": "assay:3"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ons was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differenti", "ognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted ch"], "order_basis": "paper_text_order:1225", "id": "assay:4"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["etected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expr", "moted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhance"], "order_basis": "paper_text_order:1234", "id": "assay:5"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mec"], "order_basis": "paper_text_order:1389", "id": "assay:6"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["terials and methods Human tissue samples and microarray The tissue microarray was constructed by Out", "man tissue samples and microarray The tissue microarray was constructed by Outdo Biotech Company (Sh", "ogists calculated the staining score of each microarray tissue, and the average score was considered"], "order_basis": "paper_text_order:3006", "id": "assay:7"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["logrank_test"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The Kaplan‒Meier method and the log-rank test were applied to estimate overall survival (OS) and disease-free survival (DFS). 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