1. NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer.
- Author
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Guo H, Golczer G, Wittner BS, Langenbucher A, Zachariah M, Dubash TD, Hong X, Comaills V, Burr R, Ebright RY, Horwitz E, Vuille JA, Hajizadeh S, Wiley DF, Reeves BA, Zhang JM, Niederhoffer KL, Lu C, Wesley B, Ho U, Nieman LT, Toner M, Vasudevan S, Zou L, Mostoslavsky R, Maheswaran S, Lawrence MS, and Haber DA
- Subjects
- 3' Untranslated Regions, Animals, Antineoplastic Agents pharmacology, Binding Sites, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Chromatin Assembly and Disassembly, Female, Gene Expression Regulation, Neoplastic, Genomic Instability, HEK293 Cells, Humans, Immediate-Early Proteins genetics, Indoles pharmacology, MCF-7 Cells, Mice, Inbred NOD, Mice, SCID, Neoplastic Cells, Circulating drug effects, Neoplastic Cells, Circulating pathology, Nuclear Receptor Subfamily 4, Group A, Member 1 antagonists & inhibitors, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Phenylacetates pharmacology, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-fos metabolism, R-Loop Structures, RNA Polymerase II genetics, RNA Polymerase II metabolism, Signal Transduction, Transcription Elongation, Genetic, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Mice, Breast Neoplasms metabolism, Cell Proliferation drug effects, Immediate-Early Proteins metabolism, Mitosis drug effects, Neoplastic Cells, Circulating metabolism, Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism
- Abstract
Deregulation of oncogenic signals in cancer triggers replication stress. Immediate early genes (IEGs) are rapidly and transiently expressed following stressful signals, contributing to an integrated response. Here, we find that the orphan nuclear receptor NR4A1 localizes across the gene body and 3' UTR of IEGs, where it inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes immediate dissociation of NR4A1 and a burst of transcriptionally poised IEG expression. Ectopic expression of NR4A1 enhances tumorigenesis by breast cancer cells, while its deletion leads to massive chromosomal instability and proliferative failure, driven by deregulated expression of its IEG target, FOS. Approximately half of breast and other primary cancers exhibit accessible chromatin domains at IEG gene bodies, consistent with this stress-regulatory pathway. Cancers that have retained this mechanism in adapting to oncogenic replication stress may be dependent on NR4A1 for their proliferation., Competing Interests: Declaration of interests Massachusetts General Hospital (MGH) has applied for patents regarding the CTC-iChip technology and CTC detection signatures. M.T., D.A.H., and S.M. are cofounders and have equity in Tell-Bio, which is not related to this work. The interests of these authors were reviewed and managed by MGH and Partners HealthCare in accordance with their conflict of interest policies. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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