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Nuclear receptors in cancer — uncovering new and evolving roles through genomic analysis

Nature Reviews Genetics volume 19, pages 160–174 (2018)Cite this article

Subjects

Key Points

  • Genomic approaches are uncovering new roles for nuclear receptors (NRs) in cancer and are implicating NRs in cancer that were previously known to play roles in other biological processes.

  • Genomic technologies have provided researchers with an unprecedented volume of information that allows them to integrate various genomic data sets to obtain a wider picture of NR action on the genome.

  • Genomic assays have revealed how the androgen receptor (AR) is reprogrammed upon transformation and how AR binding and target gene expression patterns change in castration-resistant prostate cancer.

  • Cistromic data sets reveal novel evidence of crosstalk between NRs, most notably between a number of different NRs and the oestrogen receptor to regulate transcriptional processes in breast cancer.

  • New evidence has emerged to support cancer-related functions for the adopted NRs that previously were studied in metabolic contexts.

Abstract

Nuclear receptors (NRs) have historically been at the forefront of cancer research, where they are known to act as critical regulators of disease. They also serve as biomarkers for tumour subclassification and targets for hormone therapy. However, most tumour types express extensive repertoires of NRs, whose interactions provide multiple paths for disease progression and offer potentially untapped mechanisms for therapeutic interventions. Recently, next-generation sequencing technologies have provided genome-wide insights into the complex interplay of NR transcriptional networks and their contribution to the development and progression of cancer. These findings have altered the traditional understanding of NR activities in oncogenesis.

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Figure 1: Nuclear receptors can be grouped according to their associated ligand and are involved in many forms of cancer.
Figure 2: Generating an integrated genomic view of the role of NR function in cancers and potential utilization in patient stratification.
Figure 3: Regulatory patterns and crosstalk of two activated nuclear receptors.

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Acknowledgements

The authors thank M. Forde for technical assistance in creating Fig. 3.

Author information

Authors and Affiliations

  1. and Departments of Human Genetics and Medicine, Institute for Genomics and Systems Biology, Institute for Molecular Engineering, University of Chicago, Chicago, 60637, Illinois, USA

    Vineet K. Dhiman, Michael J. Bolt & Kevin P. White

  2. Tempus Labs, 600 West Chicago Ave., Chicago, 60654, Illinois, USA

    Kevin P. White

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Contributions

V.K.D. and M.B. researched data for the article. V.K.D., M.B. and K.P.W. discussed the content of the article and reviewed and/or edited the manuscript before submission. All authors contributed to writing the article.

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Correspondence to Kevin P. White.

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Glossary

Ligands

Hydrophobic molecules that bind nuclear receptors and induce a conformational change in the receptor, which results in recruitment of co-regulator complexes.

Chromatin

A highly condensed structure of DNA that is associated with histone proteins and other DNA binding proteins.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). The combination of chromatin immunoprecipitation (ChIP) experiments with high-throughput sequencing to quantitatively analyse protein targeting or chromatin modifications across the entire genome.

DNase I–sequencing

DNase I digestion followed by sequencing. A method that distinguishes open chromatin regions based on their hypersensitivity to DNase I digestion. Sequencing these genomic fragments can generate genome-wide maps of chromatin accessibility.

ATAC-seq

Assay for transposase-accessible chromatin using sequencing. An experimental technique used to study chromatin accessibility that uses transposase Tn5 to cut exposed regions of the DNA.

RNA sequencing

(RNA-seq). An experimental protocol that uses next-generation sequencing technologies to sequence the RNA molecules within a biological sample in an effort to determine the primary sequence and relative abundance of each RNA.

Transcriptional profiling

The quantification of the expression of thousands of genes at once to create a global assessment of cellular function.

Cistrome

A term used to describe the set of cis-acting targets of trans-acting factors on a genome-wide scale, which are typically identified through the use of chromatin immunoprecipitation followed by sequencing and chromatin immunoprecipitation followed by microarray assays.

Global run-on sequencing

(GRO-seq). An assay used to identify and quantify nascent transcribed RNA (that is, transcripts that were initiated at the time of nuclei isolation) throughout the genome using deep sequencing.

Pioneer factor

A protein that binds condensed chromatin before the binding of other proteins and is important in the recruitment of other transcription factors and chromatin modifiers to help initiate transcription.

Enhancer RNA

A class of short non-coding RNA molecules that are transcribed from the DNA sequence of enhancer regions. It remains unclear whether they merely represent enhancer activation or have a functional significance.

ChIP–chip

Chromatin immunoprecipitation (ChIP) experiments combined with DNA microarrays to profile protein targeting or chromatin modifications over large genomic regions.

Transcriptome

The set of all mRNA molecules in any given cell or population of cells.

DNase I hypersensitivity

Pertains to regions of the genome that are sensitive to the binding of, and resulting cleavage by, the enzyme DNase I. This accessibility to DNase I is indicative of an open chromatin state that is permissive for transcription factor binding.

Warburg effect

The observation by Warburg in the 1920s that, in contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate energy, tumour cells exhibit increased aerobic glycolysis and use of glucose. Although aerobic glycolysis was initially proposed by Warburg to be due to mitochondrial impairment, recent studies have shown a preferential switch to glycolysis in tumour cells with functional mitochondria.

Promoter pausing

A method used by the cell to regulate active transcription. By pausing RNA polymerase II, active transcription is stopped until external stimuli are present to signal transcription elongation to proceed.

Precision medicine

An approach to medical care that is designed and optimized based on each individual, rather than relying solely on therapeutic approaches that are based on general population characteristics from broad epidemiological studies.

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Dhiman, V., Bolt, M. & White, K. Nuclear receptors in cancer — uncovering new and evolving roles through genomic analysis. Nat Rev Genet 19, 160–174 (2018). https://doi.org/10.1038/nrg.2017.102

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