Abstract 3004: Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms
Keenan, MM; Liu, B; Tang, X; Wu, J; Cyr, D; Stevens, RD; Ilkayeva, O; Lucas, J; Muoio, DM; Kim, SY; Chi, J-T
Published in: Cancer Research
To become established as a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. While many stress-signaling mechanisms have been well-studied, much remains unknown about how tumor cells survive these stresses during tumor progression. To identify genes that modulate cellular survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that the genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis through both metabolic and transcriptional mechanisms. First, while depleting α-ketoglutarate in control cells, hypoxia unexpectedly increased levels of α-ketoglutarate in the cells depleted of ACC1 or ACLY. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis in a mitochondria-dependent manner. Second, loss of ACLY or ACC1 reduced protein levels and activity of the oncogenic transcription factor ETV4. Silencing of ETV4 protected cells from hypoxia-induced apoptosis and triggered remarkably similar global transcriptional responses as with silenced ACLY or ACC1. Importantly, within tumor expression datasets, ETV4 transcriptional activity was highly correlated with ACLY or ACC1 gene expression signatures. Therefore, ETV4 acted as a key regulator of the transcriptional output of lipogenic activity via ACLY or ACC1. These results reveal a novel interconnectedness between cellular metabolic and transcriptional responses for life or death decisions under stress. Since lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.Citation Format: Melissa M. Keenan, Beiyu Liu, Xiaohu Tang, Jianli Wu, Derek Cyr, Robert D. Stevens, Olga Ilkayeva, Joseph Lucas, Deborah M. Muoio, So Young Kim, Jen-Tsan Chi. Contextual RNAi screen identifies ACLY and ACC1 as mediators of hypoxia-induced apoptosis through metabolic and transcriptional mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3004. doi:10.1158/1538-7445.AM2015-3004
