Circadian Gene cry Controls Tumorigenesis through Modulation of Myc Accumulation in Glioblastoma Cells

Abstract

Glioblastoma (GB) is the most frequent malignant brain tumor among adults and currently there is no effective treatment. This aggressive tumor grows fast and spreads through the brain causing death in 15 months. GB cells display a high mutation rate and generate a heterogeneous population of tumoral cells that are genetically distinct. Thus, the contribution of genes and signaling pathways relevant for GB progression is of great relevance. We used a Drosophila model of GB that reproduces the features of human GB and describe the upregulation of the circadian gene cry in GB patients and in a Drosophila GB model. We studied the contribution of cry to the expansion of GB cells and the neurodegeneration and premature death caused by GB, and we determined that cry is required for GB progression. Moreover, we determined that the PI3K pathway regulates cry expression in GB cells, and in turn, cry is necessary and sufficient to promote Myc accumulation in GB. These results contribute to understanding the mechanisms underlying GB malignancy and lethality, and describe a novel role of Cry in GB cells.

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…In glioblastoma cells, the PI3K pathway regulates Cry expression. CRY is necessary and sufficient to promote the accumulation of oncogene Myc 88 . PI3K/AKT pathway could also be regulated via tyrosine kinase AXL, which is the transcriptional target of REV‐ERBβ in glioblastoma cells 89 .…”

“…CRY is necessary and sufficient to promote the accumulation of oncogene Myc. 88 PI3K/AKT pathway could also be regulated via tyrosine kinase AXL, which is the transcriptional target of REV‐ERBβ in glioblastoma cells. 89 The core circadian clock gene Bmal1 knockdown elevated cell invasion and migration through phosphorylated‐AKT and matrix metalloproteinase‐2 (MMP‐2) accumulation.…”

Different Approaches to Study Molecular Blueprint and Biological Behavior of Brain Tumors: Editorial to the Special Issue “Advances in Molecular Genetics of Brain Tumors”

“…Moreover, studies also reported tumorigenesis mechanisms controlled by the circadian gene cry [ 7 ]. Circadian rhythm regulation [ 8 ] has only recently been introduced in cancer research.…”