Abstract A017: Bidirectional signaling between mitochondria and the nucleus dictates epigenetic rewiring to drive tumorigenesis

Abstract Cancer cells have acquired the ability to sense and adapt to varying conditions of nutrient sources in the tumor microenvironment. Mitochondria lay at the core of cellular metabolism, whereas the nucleus integrates cellular and environmental signals to activate gene transcription that alter cell function and cell fate. However, it remains largely unexplored how mitochondrial metabolic enzymes and nuclear transcriptional machineries communicate to drive gene regulation in response to metabolic stress. Biochemical screening identified a TCA cycle enzyme aconitase (ACO2), which functions as a critical mitochondrial regulator of de novo lipogenesis to sustain prostate tumor growth. Metabolic isotope tracing experiments revealed that the ACO2 enzyme promotes citrate biosynthesis required for de novo lipogenesis by reductive carboxylation of alpha-ketoglutarate generated from glutamine. Proteomics studies identified an acetylation mark lysine258 on ACO2 that induces increased enzymatic activity, whereas acetylation deficient Lys258Arg-ACO2 mutant was inactive, and failed to promote lipogenesis and tumor growth. To uncover nuclear signals that may stimulate ACO2 activity, we identified transcriptional suppression of a mitochondrial deacetylase SIRT3 by AR and its coregulator SRC-2, thereby preserving enhanced K258Ac mark on ACO2 facilitating increased lipogenesis. Interestingly our spontaneous bone metastatic mouse studies revealed that increased ACO2 activity regulated by the SIRT3/SRC-2 axis functions as a predominant survival factor for prostate tumors in the early stages of homing and colonization during bone metastasis, suggesting this pathway may be essential for metabolic adaptation in hostile microenvironment. Next, to investigate the biochemical control of gene transcription that may support tumor cell adaptation in the hostile microenvironment, we found a potential metabolic pathway that may support acetyl-CoA synthesis in the nucleus. Reversible enzymes IDH2 and ACO2 which can generate citrate from alpha-ketoglutarate to produce acetyl CoA were found to be localized in the nucleus. Interestingly, ablation of ACO2 and/or IDH2 was sufficient to significantly reduce several histone acetylation marks such as H3K9ac and H3K14ac. In isolated intact nucleus, these marks could be increased by addition of alpha-ketoglutarate thereby increasing the overall chromatin accessibility, however loss of ACO2 or IDH2 abrogated the effect, implying these enzymes are required to generate acetyl CoA in the nucleus independent of mitochondrial contribution. ATAC-seq analysis further revealed genetic inhibition of ACO2 significantly reduced chromatin accessibility with an approximate loss of 16626 peaks and gain of only 486 peaks compared to control (WT) cells. Our findings indicate a potential metabolic control in the nucleus that may regulate chromatin accessibility required for gene activation to favor tumor cell adaptation in a hostile microenvironment. This work is supported by the funds from NIH (R01CA252092 and DP2CA260421) to S.D. Citation Format: Abhisha Sawant Dessai, Nadya Elhalawany, Eriko Katsuta, Christian Prechtl, Spencer Rosario, Bert W. O’Malley, Xiang H. Zhang, Subhamoy Dasgupta. Bidirectional signaling between mitochondria and the nucleus dictates epigenetic rewiring to drive tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A017.