Research Projects

Altered energy metabolism represents as one of the ‘hallmarks of cancer’. Oncogene activation in cancer cells leads to a significant surge in ATP requirement and thereby resulting in a metabolic stress. However, cancer cells alleviates this metabolic stress by elevating autophagy and shifting the metabolic preference from oxidative phosphorylation toward aerobic glycolysis (‘Warburg effect’). The phenomenon is supported by either up-regulation of glucose transporters thus aiding enhanced glucose consumption by cancer cells or increasing catalytic activities of multiple cytosolic enzymes involved in glucose catabolism. The metabolic reprogramming can thus represent a suitable therapeutic target in many cancer types. Enolase 1 (ENO1), a highly conserved and one of the most abundantly expressed cytosolic proteins, is a key glycolytic enzyme. ENO1 can also exert various other cell functions depending on its sub-cellular localization. For example, a splice variant of ENO1, MBP1 (c-myc promoter binding protein), is localized in the nucleus and transcriptionally supresses c-Myc expression. Interestingly, c-Myc can transcriptionally activate almost all glycolytic genes. Epstein-Barr virus (EBV), the first human oncogenic virus identified, is associated with 1% of total cancers worldwide including several B-cell neoplasms. A hallmark of EBV infection is its capacity to transform quiescent B-lymphocytes into hyper-proliferating B-cell blasts, which in turn establishes latency programs accompanied by differential expressions of viral oncoproteins without inducing infectious virus particles. EBNA3C, belongs to EBNA3 family proteins and one of the key viral oncoproteins required for efficient B-cell transformation, is typically expressed in latency III program linked to immunoblastic lymphomas and in vitro generated lymphoblastoid cell lines (LCLs). Our preliminary mass-spectrometry analyses reveals that EBNA3C co-immuprecipitated with ENO1 in LCLs. The interaction was further validated using heterologous EBNA3C overexpressing system in BJAB cells. Moreover, reanalyses of several RNA-Seq and ChIP-Seq data (our unpublished results as well as data from public domains) demonstrate that upon EBV infection ENO1 transcript is significantly upregulated, transcription of which probably be regulated by coordinated actions of latent oncoprotein EBNALP, B-cell specific transcription factors cMyc and RUNX3 along with histone super-enhancer mark H3K27ac. Although metabolic reprogramming represents as key underlying mechanism for EBV-mediated oncogenesis, the role of ENO1 has not yet been studied in this context. In these lines of evidence, herein, we aim to identify and mechanistically validate the role of ENO1 in regulating metabolic activities during EBV induced B-cell lymphomagenesis. In future, the outcome of the results may expand the current therapeutic treatment through targeting ENO1 expression/activity in several EBV-positive B-cell neoplasms.