Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

Bladder cancer (BCa) is the most common malignancy of the urinary system in the United States. Most patients present with non-muscle invasive bladder cancer (NMIBC) that is treated with bladder preserving approaches. However, recurrence is high with a 50% chance to progression into muscle invasive bladder cancer (MIBC). Patients with MI disease are treated with aggressive surgery and/or systemic chemo-radiation, and more recently immune- and targeted therapies. Patients with BCa require life-long surveillance with expensive imaging, and repeated treatment courses, making BCa one of the most expensive malignancies throughout the patients’ lifespan. BCa therapies have been stagnant for almost four decades until 2016 when new immune and targeted therapies were approved for patients with locally advanced, recurrent, or metastatic disease, with an overall response of 15-29%. Thus, better understanding of the pathobiology of BCa is needed to identify actionable targets and develop novel therapeutics. In this respect, we have identified histone lysine demethylase 4A (KDM4A), also known as Jumanji D2A (JMJD2A) as a BCa onco-protein. We found that the expression of nuclear KDM4A significantly correlated with disease stage in patients’ tumors and in tobacco carcinogen-induced murine bladder tumors. KDM4A transcript expression significantly increased in bladder tumors compared to normal in TCGA data and three independent publicly available datasets. Knockdown of KDM4A in BCa cell lines significantly inhibited their proliferation and invasiveness. Interestingly, KDM4A transcripts exhibited significant inverse correlation with BCa tumor suppressor SPARC in five independent datasets. In addition, using phenotypic screening and computational modeling, we found that KDM4A is a direct target of verteporfin, a potent inducer of SPARC expression in BCa cell lines. Mechanistically, knockdown of KDM4A in BCa cell lines increased SPARC expression, whereas its overexpression inhibited basal and verteporfin-induced SPARC expression. Chromatin immune-precipitation (ChIP) assays indicated that verteporfin significantly inhibited the association of KDM4A with SPARC promoter. Together, our data underscore the oncogenic role of KDM4A in BCa and its potential as an actionable target. Citation Format: Bailey O. Warren, Ammar Y. Abdelfattah, Alia Ghoneum, Freddie Salsbury, Neveen A. Said. Role of KDM4A in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 547.