Renhao Xue

Identification of a Prognostic Signature for Ovarian Cancer Based on Ubiquitin-Related Genes Suggesting a Potential Role for FBXO9

Background: Ovarian cancer (OV) is associated with high mortality and poses challenges in diagnosis and prognosis prediction. Ubiquitin-related genes (UbRGs) are involved in the initiation and progression of cancers, but have still not been utilized for diagnosis and prognosis of OV. Methods: K48-linked ubiquitination in ovarian tissues from our OV and control cohort was assessed using immunohistochemistry. UbRGs, including ubiquitin and ubiquitin-like regulators, were screened based on the TCGA-OV and GTEx database. Univariate Cox regression analysis identified survival-associated UbRGs. A risk model was established using the LASSO regression and multivariate Cox regression analysis. The relationship between UbRGs and immune cell infiltration, tumor mutational burden, drug sensitivity, and immune checkpoint was determined using the CIBERSORT, ESTIMATE, and Maftools algorithms, based on the Genomics of Drug Sensitivity in Cancer and TCGA-OV databases. GEPIA2.0 was used to analyze the correlation between FBXO9/UBD and DNA damage repair-related genes. Finally, FBXO9 and UBD were accessed in tissues or cells using immunohistochemistry, qPCR, and Western blot. Results: We confirmed the crucial role for ubiquitination in OV as a significant decrease of K48-linked ubiquitination was observed in primary OV lesions. We identified a prognostic signature utilizing two specific UbRGs, FBXO9 and UBD. The risk score obtained from this signature accurately predicted the overall survival of TCGA-OV training dataset and GSE32062 validation dataset. Furthermore, this risk score also showed association with immunocyte infiltration and drug sensitivity, revealing potential mechanisms for ubiquitination mediated OV risk. In addition, FBXO9, but not UBD, was found to be downregulated in OV and positively correlated with DNA damage repair pathways, suggesting FBXO9 as a potential cancer suppressor, likely via facilitating DNA damage repair. Conclusions: We identified and validated a signature of UbRGs that accurately predicts the prognosis, offers valuable guidance for optimizing chemotherapy and targeted therapies, and suggests a potential role for FBXO9 in OV.

Profiling of RUVBL2 ‐Induced Transcriptome Alterations Highlights a Critical Role for Chromatin Remodeling in Ovarian Cancer

ABSTRACT Cancerous transcriptome alterations in carcinoma cells could be originated from either genetic copy number changes or epigenetic reprogramming. Ovarian cancer (OV) is the most malignant gynecologic tumor, known for high aneuploidy with robust copy number alterations. However, low aneuploidy ovarian tumors are also frequently found, indicating an essential contribution of epigenetic factors during tumorigenesis and cancer development. Chromatin remodeling modulates the transcriptome epigenetically in a variety of cancer types, but its role in OV is still unclear. Hence, we investigated a cohort of 102 OV patients, analyzed transcriptomic and clinical data from public databases, and performed cellular experiments. We found that RUVBL2, a subunit of the INO80 complex, functions as the key oncogenic chromatin remodeler in OV. RUVBL2 is upregulated in tumors, particularly in low‐aneuploidy cases, and is associated with poor prognosis. RUVBL2 drives nucleosome dynamics and elevates chromatin accessibility selectively at promoter regions. The landscape of RUVBL2‐dependent modulation of chromatin accessibility and the transcriptome exhibits activation of various transcription factors, especially the AP‐1 family, and upregulation of a series of key genes, including CDKN3 , MYBL2 , and ZNF144 , resulting in mediation of cell cycle and Hippo signaling pathway to promote DNA synthesis and cell proliferation. Hence, RUVBL2‐dependent chromatin remodeling plays a key role in oncogenic reprogramming of the transcriptome in OV. These findings provide novel insights into the molecular etiology of OV and disclose potential biomarkers and drug targets.