Abstract B05: N-Myc downstream regulated gene 2 is a novel regulator of lipid metabolism and ubiquitin-proteasome system in cancer

Abstract

Abstract Background and Aims: Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect metabolism of cancer cells. NDRG2 (N-Myc downstream regulated gene 2) is a newly identified tumor suppressor gene in our lab and others. We reported previously that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-MYC, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic enzymes involved in glycolysis and glutaminolysis, which fuels the bioenergy and biomaterials needed for cancer proliferation and progress. Our recent studies showed that NDRG2 is involved in cell apoptosis or survival when the cells are challenged by various stress factors such as hypoxia and lipotoxicity. However, whether NDRG2 is implicated in lipid metabolism and other cellular process is unknown. Methods: We explored the role of NDRG2 in lipid metabolism by using Oil red staining of the liver tissues from Ndrg2 mouse v.s. wild-type counterpart. We also examined the effect of Ndrg2 on the transcription of the proteasome subunits by RT-PCR, its effect on the proteasome activity by protease activity assay, as well as Nrf1 relevance in such regulation, through using the liver tissues of mouse and NDRG2-overxepressing HepG2 cells. Results: Ndrg2 mice exhibited lipid accumulation in liver compared with the wild-type counterpart. Besides, the proteasome genes transcription were upregulated in Ndrg2 liver tissue but downregulated in NDRG2-overexpressing HepG2 cells. Moreover, NDRG2-overexpression suppressed the proteasome activity in HepG2 cells. Such effect is comparable to, but not additive with, siRNA-mediated silence of Nrf1, a well-known proteasome regulator that coordinately induces proteasome gene transcription. This implies that NDRG2 exerts its role by inhibiting Nrf1. Finally, we demonstrated that NDRG2 interacts with Nrf1 and promotes its downregulation. Conclusion: We demonstrated for the first time that NDRG2 is a critical regulator of lipid metabolism and proteasome activity. NDRG2 inhibits the proteasome activity probably by interacting with Nrf1 and promoting its downregulation. Note: This abstract was not presented at the conference. Citation Format: Libo Yao, Xia Li, Xiping Liu, Yi Ru, Mei Zhang. N-Myc downstream regulated gene 2 is a novel regulator of lipid metabolism and ubiquitin-proteasome system in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B05.