Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain

PLoS One. 2014 Oct 16;9(10):e110610. doi: 10.1371/journal.pone.0110610. eCollection 2014.

Abstract

Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large-scale analysis of mRNA expression. All caspases were analyzed in terms of co-expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Brain / metabolism
  • Brain / pathology
  • Caspase 1 / biosynthesis*
  • Caspase 1 / metabolism
  • Caspase 10 / biosynthesis*
  • Caspase 10 / metabolism
  • Caspase 2 / biosynthesis*
  • Caspase 2 / metabolism
  • Caspase 3 / biosynthesis
  • Caspase 3 / metabolism
  • Caspase 9 / biosynthesis*
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Cysteine Endopeptidases / biosynthesis*
  • Cysteine Endopeptidases / metabolism
  • Gene Expression Regulation, Neoplastic / genetics
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Homeostasis
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Organ Specificity
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics

Substances

  • RNA, Messenger
  • Cholesterol
  • CASP2 protein, human
  • Caspase 10
  • Caspase 2
  • Caspase 3
  • Caspase 9
  • Cysteine Endopeptidases
  • Caspase 1
  • CASP10 protein, human

Grants and funding

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC) (IG-10437) and Programma di ricerca scientifica di rilevante interesse nazionale (PRIN) (Progetto 2010W4J4RM_002) to CB. AT received a fellowship from AIRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.