Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival.
Hypoxia in the microenvironment of many solid tumours is an important determinant of malignant progression. The ISR (integrated stress response) protects cells from the ER (endoplasmic reticulum) stress caused by severe hypoxia. Likewise, autophagy is a mechanism by which cancer cells can evade hypoxic cell death. In the present paper we report that the autophagy-initiating kinase ULK1 (UNC51-like kinase 1) is a direct transcriptional target of ATF4 (activating transcription factor 4), which drives the expression of ULK1 mRNA and protein in severe hypoxia and ER stress. We demonstrate that ULK1 is required for autophagy in severe hypoxia and that ablation of ULK1 causes caspase-3/7-independent cell death. Furthermore, we report that ULK1 expression is associated with a poor prognosis in breast cancer. Collectively, the findings of the present study identify transcriptional up-regulation of ULK1 as a novel arm of the ISR, and suggest ULK1 as a potentially effective target for cancer therapy.
Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
Luke R G
LR
Pike
Dean C
DC
Singleton
Francesca
F
Buffa
Olga
O
Abramczyk
Kanchan
K
Phadwal
Ji-Liang
JL
Li
Anna Katharina
AK
Simon
James T
JT
Murray
Adrian L
AL
Harris
D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071189:Autophagy-Related Protein-1 Homolog; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D015999:Multivariate Analysis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D015533:Transcriptional Activation; D015854:Up-Regulation
C497109:ATF4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051701:Activating Transcription Factor 4; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human