Oncogenic Chromatin Modifier KAT2A Activates MCT1 to Drive the Glycolytic Process and Tumor Progression in Renal Cell Carcinoma

Abstract

ObjectivesThis study aims to investigate the underlying mechanisms of KAT2A/MCT1 axis in renal cell carcinoma (RCC), providing potential therapeutic targets.MethodsWe obtained the expression data of KAT2A and MCT1 from The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) and International Cancer Genome Consortium (ICGC) databases. Differential analysis was conducted via the limma package. The CCK8 assay, soft agar assay, clone formation assay, and patients-derived organoid models were used to detect cell growth. The transwell and wound-healing assays were utilized to detect cell migration. The in vitro and in vivo assays were further conducted to assess the oncogenic roles of KAT2A. The transcriptome sequencing and chromatin immunoprecipitation (ChIP) sequencing were conducted to screen KAT2A downstream targets. The dose-effect curves were used to detect the 50% inhibiting concentration (IC50) of AZD3965. Data analysis was performed in the Graphpad Prism (Version 8.3.0) and R software (Version 3.6.1).ResultsOur study found that KAT2A was highly expressed in RCC versus normal samples. Prognostic analysis indicated that a high KAT2A was an independent biomarker and associated with poor survival outcomes. KAT2A could promote RCC proliferation and distal metastasis in vitro and in vivo. Transcriptome analysis and ChIP-seq were combined to find that KAT2A mainly regulated the glycolytic process. Validation and rescue assays revealed that MCT1 was the downstream target of KAT2A, and KAT2A depended on MCT1 to promote RCC malignant phenotypes. Lastly, MCT1 inhibitor (AZD3965) was effective to treat KAT2A-induced RCC progression.ConclusionOur study indicated that KAT2A was an oncogenic chromatin modifier that promotes RCC progression by inducing MCT1 expression. We proposed that MCT1 inhibitor (AZD3965) was useful for suppressing RCC.

In Vivo Anticancer Activity of AZD3965: A Systematic Review

“…After a full analysis, twelve studies were considered to fit into the aim of assessing AZD3965 antitumor efficacy in vivo. Within those studies, two were performed using cell lines from small cell lung cancer [ 27 , 32 ], six used non-Hodgkin’s lymphoma cells [ 19 , 28 , 33 , 35 , 36 , 37 ], two used breast cancer cells [ 37 , 38 ], one used head and neck squamous cell carcinoma cells [ 39 ], one used lung squamous cell carcinoma cells [ 40 ], one used colorectal carcinoma cells [ 36 ] and one used renal cell carcinoma cells [ 41 ]. Studies reported administration of AZD3965 as monotherapy alone [ 19 , 27 , 35 , 36 , 37 , 38 , 41 ], or monotherapy and combined with either radiation (2Gy for 3 days) [ 32 ] or other pharmacological therapy—doxorubicin or rituximab [ 33 ], BAY-2243 [ 28 ], simvastatin [ 39 ] or JNJ-605 [ 40 ], all compared to vehicle control.…”

“…All studies used mouse models to test AZD3965. Regarding gender, two studies used male mice [ 27 , 41 ], one did not report gender [ 28 ], and the remaining used female mice. Animal age ranged from 4 to 14 weeks, although, on average, experiments were conducted in adult mice (over 8 weeks).…”

“…The most commonly used strains were SCID and NSG and treatment was performed up to 43 days. Tumor induction was performed orthotopically in two studies [ 28 , 38 ] and non-orthotopically (subcutaneous injection) in the remaining studies [ 19 , 27 , 32 , 33 , 35 , 36 , 37 , 39 , 40 , 41 ]. Four to eleven animals were used per group, and groups treated with AZD3965 received the drug when tumor reached a volume between 100 and 500 mm 3 .…”

“…In the presently selected studies, the authors performed experiments where AZD3965 was used as monotherapy [ 19 , 27 , 35 , 36 , 37 , 38 , 40 ], as monotherapy and combined with other therapies [ 28 , 32 , 33 , 39 ], and combined therapy exclusively [ 41 ], with a control group always included. After a full analysis of each publication, we evaluated the quality of the studies.…”

“…Guo et al tested AZD3965 in KAT2A-overexpressing renal cell cancer xenografts. Inhibition of MCT1 with AZD3965 resulted in suppression of tumor growth induced by KAT2A (lysine acetyltransferase 2A, involved in the mediation of post-translational modification in histone H3 [ 46 ]) [ 41 ].…”