Dataset Information

OTUD3-Mediated Stabilization of SLC7A11 Drives Sunitinib Resistance by Suppressing Ferroptosis in Clear Cell Renal Cell Carcinoma

ABSTRACT: After cell lysis, the global proteomes of wild-type 786O and OTUD3-knockdown (KD) 786O cell lines were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Label-free quantification (LFQ) was employed for comparative protein quantification, and tandem mass spectrometry data were acquired in data-dependent acquisition (DDA) mode to prioritize high-abundance precursor ions for fragmentation

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Tian Xu

LAB HEAD: Weihong Tan

PROVIDER: PXD064004 | Pride | 2025-08-15

REPOSITORIES: Pride

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OTUD3-mediated stabilization of SLC7A11 drives sunitinib resistance by suppressing ferroptosis in clear cell renal cell carcinoma.

Xu Tian T Liu Huimin H Ling Neng N Chen Daiquan D Dai Jing J Chen Wenjing W Li Yuxuan Y Gao Xirong X Zhai Wei W Ye Mao M Sun Yang Y Tan Weihong W

Cancer letters 20250725

Clear cell renal cell carcinoma (ccRCC), as the main type of RCC was treated with tyrosine kinase inhibitor (TKI) at the late stage. While drug resistance is the main challenge for TKIs like sunitinib, and the underline mechanisms remain unclear. Here, we found that OTUD3 is over-expressed in ccRCC and promotes sunitinib resistance in tumor cells. OTUD3 deubiquitinates the cystine/glutamate transporter SLC7A11 and protect it from proteasome degradation, which promotes cystine transport into cell ...[more]

PMID: 40716486

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Project description:BackgroundGenetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy.Patients and methodsMulti-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; ClinicalTrials.gov identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R.ResultsUnsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment.ConclusionsDemonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for biomarker research.

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