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PSAT1 mediated changes in gene expression in EGF-stimulated lung cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173270 | GEO | 2024/04/23

REPOSITORIES: GEO

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Project description:Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions. Parental MDA-MB-231 cells and MDA-MB-231(SA) cells were cultured in cell culture flasks. RNA was isolated in order to compare the gene expression profiles of these cell variants. Total of two samples. No replicates.

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PSAT1 mediated changes in gene expression in EGF-stimulated lung cancer

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