Methylation Silencing of ULK2, an Autophagy Gene, Is Essential for Astrocyte Transformation and Tumor Growth

Abstract

Background: Autophagy, a catabolic degradation process, has been shown to promote and inhibit cell growth. Results: ULK2, an upstream autophagy initiator, is silenced by methylation in glioblastoma, and its ectopic expression inhibited astrocyte transformation and glioma cell growth through autophagy. Conclusion: ULK2 down-regulation is important for the astrocyte transformation and tumor growth. Significance: Autophagy inhibition is essential for glioma development.

PI3K/Akt/mTOR activation by suppression of ELK3 mediates chemosensitivity of MDA-MB-231 cells to doxorubicin by inhibiting autophagy

“…DAPK1 and ATG10, which stimulate autophagy [16,17], were activated, whereas several genes known to activate autophagy, such as DRAM1, ULK2, BCL2L1, EPG5, and NPC1, were suppressed in ELK3 KD [18][19][20][21][22][23][24][25] (Fig. 1A).…”

Emerging strategies to effectively target autophagy in cancer

“…101 Methylation also has a role in autophagy regulation, with a genome-wide methylation analysis revealing hyper-methylation of the ULK2 gene, resulting in the inhibition of autophagy in glioblastoma cells. 102 Epigenetic agents such as HDACs 85 and demethylating agents 103 have already been shown to modulate autophagy, and these new findings could guide their development further as autophagy modulators.…”

Autophagy and Tubular Cell Death in the Kidney

“…Mitochondrial permeability transition, oxidative stress and ROS can also directly promote autophagy in the ischemic kidney 27,97,98 . ULK1, a kinase with an important role in autophagy initiation, is also induced by hypoxia in kidney tissue and the lack of this protein suppresses autophagy in ischemic models 99-102 . Hypoxia causes dissociation of mTOR and ULK1 leading to autophagy induction 99-101 .…”

“…Hypoxia causes dissociation of mTOR and ULK1 leading to autophagy induction 99-101 . In non-renal cell culture models, ULK1 interacts with mTORC1, AMPK, JNK and Beclin 1 to intervene at several steps in the autophagic and apoptotic pathways 48,99-102 . Yet another recently discovered mechanism, clusterin, a chaperone-like protein was shown to be required for autophagy induction 103 .…”