image: (A) CISD1 mRNA expression in various human normal tissues. Genotype Tissue Expression (GTEx) data for CISD1 mRNA in human normal tissues were downloaded from The Human Protein Atlas (THPA) and analyzed using GraphPad Prism. (B) CISD1 mRNA expression in various human cancer tissues. The Cancer Genome Atlas (TCGA) data for CISD1 mRNA expression across different cancer types were retrieved from THPA and analyzed using GraphPad Prism. (C) CISD1 mRNA expression levels in tumor tissues were compared with normal tissues across 33 cancer types. Differential expression analysis was conducted using GEPIA2, with a significance threshold of Q < 0.05 (Benjamini-Hochberg correction for multiple testing). Cancer types with significantly increased CISD1 expression are indicated in brown font, while those with significantly decreased expression are in blue font. N = normal tissue, and T = tumor tissue.
Credit: Caiyue Li, Zhipin Liang, Gabrielle Vontz, Connor Kent, Wenbo Ma, Lei Liu, Riya Dahal, Jovanny Zabaleta, Guoshuai Cai, Jia Zhou, Huangen Ding, Qiang Shen
Despite significant advancements in medicine, cancer remains a major health challenge and the leading cause of mortality worldwide, highlighting the urgent need for continued research to identify robust biomarkers for the early detection, prognosis, and treatment across multiple cancer types.
In a recent study, published in the Genes & Diseases journal, researchers at Louisiana State University Health Sciences Center, Tulane University, University of Florida, University of Texas Medical Branch, and Louisiana State University, provide the first comprehensive pan-cancer bioinformatics analysis determining the functions of CISD1 in multiple cancers using public patient databases, and demonstrate its potential as a multi-faceted biomarker in various cancers.
Data obtained from TCGA, GTEx, THPA, GEPIA2.0, SangerBox, cBioPortal, TIMER2.0, CAMOIP, DAVID, SRPLOT, and TISIDB databases showed significant alterations in the expression of CISD1 at both the transcriptional and translational levels in various cancers. Mutations in the CISD1 gene within the zf-CDGSH domain, especially at the A69S/V (a hotspot mutation site), in multiple cancers highlight its role in cancer initiation and progression, and its potential as a diagnostic biomarker.
High CISD1 expression was associated with poor clinical outcomes, including low survival and high mortality risk. A positive correlation between CISD1 and stemness indices in multiple cancers suggests that CISD1 promotes or maintains stem cell-like properties in cancer cells, and may serve as an indicator of stem-cell-enriched tumors, underscoring its potential role in driving tumor aggressiveness and therapeutic resistance. High expression of CISD1 along with increased stemness levels was associated with poor prognosis. Additionally, CISD1 plays a critical role in cellular bioenergetics, significantly correlating with tumor mutation burden and microsatellite instability, and ultimately poor prognosis in multiple cancers. These findings reinforce its feasibility as a potential prognostic marker.
Moreover, CISD1 expression was altered in patients undergoing immunotherapy; specifically, tumors with high CISD1 expression showed increased levels of immune checkpoint proteins, which serve as targets for immune checkpoint blockade. Since elevated immune checkpoints are considered effective immunotherapeutic targets, overexpression of CISD1 may serve as a reliable biomarker for immunotherapy, further solidifying its role as not only a diagnostic and prognostic biomarker but also as a key predictor of immunotherapy outcomes.
This study not only establishes CISD1 as a multi-faceted biomarker but also highlights its potential as a therapeutic target in multiple cancers. Therapeutic strategies targeting CISD1's iron-sulfur cluster or modulating its protein expression may hold great potential for improving cancer outcomes. Furthermore, CISD1 exhibits a dual role in cancer. While its expression is upregulated in most cancers, the expression of CISD1 was down-regulated in six types of cancer, suggesting that CISD1 may play tumor-suppressive functions in these cancers.
The authors acknowledge the lack of experimental validation as a limitation of the study and also recognize that data set heterogeneity, including variations in data processing and normalization across platforms, could have introduced unfavored biases affecting the findings of this study. However, this “systematic pan-cancer analysis lays a strong foundation for further exploring the biological functions of CISD1 in cancers”.
In conclusion, this comprehensive pan-cancer bioinformatics analysis on the role of the CISD1 gene in different aspects of tumorigenesis reveals that CISD1 could serve as a “reliable and promising diagnostic, prognostic, and immunotherapeutic biomarker in multiple cancers”.
Reference
Title of the original paper: Exploring CISD1 as a multifaceted biomarker in cancer: Implications for diagnosis, prognosis, and immunotherapeutic response
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101677
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