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Microenvironmental-derived Regulation of HIF-Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme

ABSTRACT: The evolving and highly heterogeneous nature of malignant brain tumors underlies their limited response to therapy and poor prognosis. In addition to genetic alterations, highly dynamic processes such as transcriptional and metabolic reprograming play an important role in the development of tumor heterogeneity. The present study reports an adaptive mechanism in which the metabolic environment of malignant glioma drives transcriptional reprogramming. Multi-regional analysis of a glioblastoma patient biopsy revealed a metabolic landscape marked by varying stages of hypoxia and creatine enrichment. Creatine treatment and metabolism was further shown to promote a synergistic effect through up-regulation of the glycine-cleavage system and chemical regulation of Prolyl-Hydroxylase Domain (PHD). Consequently, creatine maintained a reduction of reactive oxygen species and change of the a-ketoglutarate/succinate ratio leading to an inhibition of the HIF-signaling in primary tumor cell lines. These effects shifted the transcriptional pattern toward a proneural subtype and reduced the rate of cell migration and invasion in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108013 | GEO | 2017/12/14

SECONDARY ACCESSION(S): PRJNA422221

REPOSITORIES: GEO

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Project description:Besides being building blocks for protein synthesis, amino acids serve a wide variety of cellular functions, including acting as metabolic intermediates for ATP generation and for redox homeostasis. Upon amino acid deprivation, free uncharged tRNAs trigger GCN2-ATF4 to mediate the well-characterized transcriptional amino acid response (AAR). However, it is not clear whether the deprivation of different individual amino acids triggers identical or distinct AARs. Here, we characterized the global transcriptional response upon deprivation of one amino acid at a time. With the exception of glycine, which was not required for the proliferation of MCF7 cells, we found that the deprivation of most amino acids triggered a shared transcriptional response that included the activation of ATF4, p53 and TXNIP. However, there was also significant heterogeneity among different individual AARs. The most dramatic transcriptional response was triggered by methionine deprivation, which activated an extensive and unique response in different cell types. We uncovered that the specific methionine-deprived transcriptional response required creatine biosynthesis. This dependency on creatine biosynthesis was caused by the consumption of S-Adenosyl-L-methionine (SAM) during creatine biosynthesis that helps to deplete SAM under methionine deprivation and reduces histone methylations. As such, the simultaneous deprivation of methionine and sources of creatine biosynthesis (either arginine or glycine) abolished the reduction of histone methylation and the methionine-specific transcriptional response. Arginine-derived ornithine was also required for the complete induction of the methionine-deprived specific gene response. Collectively, our data identify a previously unknown set of heterogeneous amino acid responses and reveal a distinct methionine-deprived transcriptional response that results from the crosstalk of arginine, glycine and methionine metabolism via arginine/glycine-dependent creatine biosynthesis. RNA was extracted by RNAeasy kits (Qiagen) from the MCF7 or PC3 cells which exposed to the control full DMEM or deprived one (or all) amino acid media for 24 or 48 hours.

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Microenvironmental-derived Regulation of HIF-Signaling Drives Transcriptional Heterogeneity in Glioblastoma Multiforme

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