Abstract
Purpose :
Uveal melanoma is a deadly cancer with high metastatic potential. Mitochondrial genetics and epigenetics are known to play a role in tumorigenesis, progression, and metastasis, while mitochondrial metabolites have recently been shown to cause changes in the nuclear epigenome. In this study, we describe the transcriptional state of genes involved in mitochondrial metabolism, chromatin remodelling, and histone modification in uveal melanoma in order to define targetable signaling pathways.
Methods :
TCGA database of 80 primary uveal melanoma cases was queried for mRNA transcript levels of key mitochondrial metabolism enzymes and mitochondrial metabolism-dependent chromatin remodeling and histone modifying enzymes. These were selected a priori based on recently described metabolically-induced chromatin changes with known transcriptional outcomes (Kopinski et al. 2019, Picard et al. 2014). Transcription levels were compared against the group mean and samples were grouped based on key enzyme transcriptional profiles.
Results :
Of the 80 analyzed samples, a third showed alterations in transcription co-activator PGC1α and citrate synthase (CS), a quarter in ATP-dependent citrate lyase (ACLY), and a fifth in mitochondrial polymerase γ (POLG). A third showed alterations in NAD-dependent deacetylases: Sirtuins 1 and 6 (SIRT1, SIRT6), of which 60% were discordant. Histone 3 lysine 9 (H3K9) demethylases (KDM3A, KDM3B, JMJD1C) were altered in a third of samples with high concordance. A quarter showed highly concordant alterations in DNA methyltransferases DNMT3A and B. Interestingly, Sirt1 expression was highly discordant with that of citrate synthase, while H3K9 methyltransferase showed discordance with H3K9 demethylases.
Conclusions :
Primary uveal melanoma samples exhibit distinct transcriptional profiles with differential expression of mitochondrial metabolism and chromatin modifying enzymes, allowing identification of potentially targetable signalling pathways. Patterns of chromatin modifying enzyme expression suggest internally consistent conditions to promote a given chromatin state, with concordant expression of enzymes with similar function and opposing expression of those with opposite function. This suggests a personalized, transcriptonal profile-based metabolic intervention to disrupt these conditions may disable functional chromatin, thus providing a therapeutic target.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.