p53 fosters metabolic reprogramming, which restricts metabolic adaptation of tumor cells under energy stress conditions. However, modulation and directionality of underlying cascades to induce or restrict metabolism are determined by the downstream target of p53. To explore the role of p53 in tumor metabolism upon metabolic stress, we performed a microarray screen in the presence or absence of p53 under glucose starvation. We observed caspase-10 to be upregulated by p53 upon metabolic stress. Caspase-10 belongs to the class of initiator caspases and is poorly understood in terms of substrate specificities. Emerging evidences also suggest intrinsic activation of caspase-10, distinct from its homologue caspase-8. Moreover, inactivating mutations as well as downregulation of caspase-10 in several carcinomas are suggestive of its role in tumorigenesis. Thus, we investigated the function of caspase-10 as a tumor suppressor. Our results indicated that caspase-10, upregulated in a p53-dependent manner in response to metabolic stress, was activated by homodimerization-induced intrinsic activation mechanism involving Adenylate Kinase 2 and FADD. We further performed a proteomic screen to identify novel caspase-10 substrates. We observed that several anabolic enzymes are caspase-10 interacting partners. However, in vitro and in vivo assays confirmed only ATP-Citrate Lyase (ACLY) as a novel substrate of caspase-10. Cleavage of ACLY by caspase-10 abrogates enzymatic conversion of cytosolic citrate to acetyl-CoA, leading to overall decrease in nucleocytosolic acetyl-CoA pool. Decrease in cytosolic acetyl-CoA levels suppress lipogenesis upon metabolic stress. Moreover, decreased levels of nuclear acetyl-CoA alter global histone acetylation. Further studies using RNAi established that alteration in histone acetylation is GCN5-dependent. Caspase-10-dependent abrogation of histone acetylation reprograms the epigenetic profile of metastatic and proliferative genes, leading to their diminished expression under metabolic stress. Concomitant suppression of both cytosolic lipogenesis and nuclear histone acetylation by caspase-10-mediated ACLY cleavage decreases proliferation capacity, migration potential and invasiveness of tumor cells. Further, studies in mouse tumor models confirmed that caspase-10 restricts tumorigenesis and metastases under metabolic stress via ACLY and GCN5. Taken together, our findings establish caspase-10 as a novel integrator of metabolism and epigenetics, by regulating acetyl-CoA levels. Hence, it functions as a tumor suppressor by disrupting lipogenesis-mediated metabolic reprogramming and GCN5-mediated epigenetic reprogramming.
Citation Format: Rajni Kumari, Sanjeev Das. Caspase-10 suppresses tumorigenesis by targeting ATP-citrate lyase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2017-1543