GSE173270
PSAT1 mediated changes in gene expression in EGF-stimulated lung cancer
In addition to supporting increased cellular metabolism for untethered neoplastic growth, recent reports have indicated that certain metabolic enzymes may exhibit alternative functions in human cancers. Despite the ability to import serine from the microenvironment, lung tumors significantly elevate expression of biosynthetic enzymes responsible for the de novo production of serine, notably phosphoserine aminotransferase 1 (PSAT1). Highlighting the relevance of PSAT1 in lung cancer, patients with increased expression demonstrated poorer overall survival, so characterizing its role in lung tumor progression may ultimately identify different therapeutic strategies targeting this disease. Our preliminary studies now demonstrate a potential alternative function, beyond serine synthesis, of PSAT1 in lung tumor cells. Specifically, we found that PSAT1 localizes to the nucleus upon epidermal growth factor stimulation [via activating EGFR mutation (PC9, inhibited by the EGFR-mutant specific inhibitor, Erlotinib) or EGF stimulation (A549, EGFR-WT)] and regulates the nuclear import of pyruvate kinase M2 (PKM2). Importantly, nuclear PKM2 has been demonstrated to directly phosphorylate histones and modify gene transcription. In further support of this functional interaction, within yeast, PKM2 association with serine synthetic enzymes resulted in pervasive chromatin remodeling and alteration in global gene expression. Therefore, our objective in this proposal is to define gene signatures promoted by PSAT1-mediated nuclear PKM2 translocation in response to EGF-signaling in human lung cancer cells. Overall design: In pursuit of this objective, we have stably-silenced PSAT1 expression in PC9 human lung cancer lines for comparison to control cells.  In total, we have two distinct sample groups with 3 replicates each (PC9: Control and PSAT1 shRNA).