A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival

Yiwen Bu; Akihiro Yoshida; Nilesh Chitnis; Brian J Altman; Feven Tameire; Amanda Oran; Victoria Gennaro; Kent E Armeson; Steven B McMahon; Gerald B Wertheim; Chi V Dang; Davide Ruggero; Constantinos Koumenis; Serge Y Fuchs; J Alan Diehl

doi:10.1038/s41556-017-0006-y

A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival

Nat Cell Biol. 2018 Jan;20(1):104-115. doi: 10.1038/s41556-017-0006-y. Epub 2017 Dec 11.

Authors

Affiliations

¹ Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
² Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
³ Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
⁵ Department of Public Health Sciences and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
⁶ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Departments of Urology and Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Biomedical Sciences, School of Veterinary Medicine, Philadelphia, PA, USA.
⁹ Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. diehl@musc.edu.

Abstract

The unfolded protein response (UPR) is a stress-activated signalling pathway that regulates cell proliferation, metabolism and survival. The circadian clock coordinates metabolism and signal transduction with light/dark cycles. We explore how UPR signalling interfaces with the circadian clock. UPR activation induces a 10 h phase shift in circadian oscillations through induction of miR-211, a PERK-inducible microRNA that transiently suppresses both Bmal1 and Clock, core circadian regulators. Molecular investigation reveals that miR-211 directly regulates Bmal1 and Clock via distinct mechanisms. Suppression of Bmal1 and Clock has the anticipated impact on expression of select circadian genes, but we also find that repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation to stresses that disrupt endoplasmic reticulum homeostasis. Our data demonstrate that c-Myc-dependent activation of the UPR inhibits Bmal1 in Burkitt's lymphoma, thereby suppressing both circadian oscillation and ongoing protein synthesis to facilitate tumour progression.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

ARNTL Transcription Factors / antagonists & inhibitors
ARNTL Transcription Factors / genetics
ARNTL Transcription Factors / metabolism
Animals
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Bone Neoplasms / genetics*
Bone Neoplasms / metabolism
Bone Neoplasms / pathology
CLOCK Proteins / antagonists & inhibitors
CLOCK Proteins / genetics
CLOCK Proteins / metabolism
Cell Line, Tumor
Cell Survival
Circadian Clocks / genetics*
Gene Expression Regulation, Neoplastic*
Heterografts
Humans
Light Signal Transduction
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
MicroRNAs / genetics*
MicroRNAs / metabolism
Osteoblasts / metabolism
Osteoblasts / pathology
Osteosarcoma / genetics*
Osteosarcoma / metabolism
Osteosarcoma / pathology
Photoperiod
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Unfolded Protein Response
eIF-2 Kinase / genetics*
eIF-2 Kinase / metabolism

Substances

ARNTL Transcription Factors
BMAL1 protein, human
MIRN211 microRNA, human
MicroRNAs
RNA, Small Interfering
CLOCK Proteins
CLOCK protein, human
EIF2AK3 protein, human
eIF-2 Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding