Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep;111(9):3155-3163.
doi: 10.1111/cas.14551. Epub 2020 Jul 21.

Nuclear microenvironment in cancer: Control through liquid-liquid phase separation

Ryu-Suke Nozawa  1 , Tatsuro Yamamoto  2 , Motoko Takahashi  1 , Hiroaki Tachiwana  2 , Reo Maruyama  3 , Toru Hirota  1 , Noriko Saitoh  2
Affiliations
Review

Nuclear microenvironment in cancer: Control through liquid-liquid phase separation

Ryu-Suke Nozawa et al. Cancer Sci. 2020 Sep.

Abstract

The eukaryotic nucleus is not a homogenous single-spaced but a highly compartmentalized organelle, partitioned by various types of membraneless structures, including nucleoli, PML bodies, paraspeckles, DNA damage foci and RNA clouds. Over the past few decades, these nuclear structures have been implicated in biological reactions such as gene regulation and DNA damage response and repair, and are thought to provide "microenvironments," facilitating these reactions in the nucleus. Notably, an altered morphology of these nuclear structures is found in many cancers, which may relate to so-called "nuclear atypia" in histological examinations. While the diagnostic significance of nuclear atypia has been established, its nature has remained largely enigmatic and awaits characterization. Here, we review the emerging biophysical principles that govern biomolecular condensate assembly in the nucleus, namely, liquid-liquid phase separation (LLPS), to investigate the nature of the nuclear microenvironment. In the nucleus, LLPS is typically driven by multivalent interactions between proteins with intrinsically disordered regions, and is also facilitated by protein interaction with nucleic acids, including nuclear non-coding RNAs. Importantly, an altered LLPS leads to dysregulation of nuclear events and epigenetics, and often to tumorigenesis and tumor progression. We further note the possibility that LLPS could represent a new therapeutic target for cancer intervention.

Keywords: chromatin structure; intrinsically disordered region/protein; liquid-liquid phase separation; non-coding RNA; nuclear microenvironment.

PubMed Disclaimer

Conflict of interest statement

R‐SN received a research grant from the Uehara Memorial Foundation, the Naito Foundation and the Vehicle Racing Commemorative Foundation. NS received a research grant from DAIZ Inc., the Uehara Memorial Foundation, the Naito Foundation, the Vehicle Racing Commemorative Foundation, the Takeda Science Foundation and the Princess Takamatsu Cancer Research Fund. MT received a research grant from the Vehicle Racing Commemorative Foundation. Other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Nuclear microenvironments and principles of their formation. A, The eukaryotic nucleus is highly compartmentalized and contains various membraneless organelles (nuclear bodies/structures). Their immuno‐stained or FISH images are shown. B, Multivalent interactions between proteins and nucleic acids trigger liquid‐liquid phase separation (LLPS). LLPS is reversible (left) and the resultant liquid droplet (yellow‐highlighted area) is dynamic (middle); however, its hyper self‐assembly causes irreversible solid aggregate formation (right)
Figure 2
Figure 2
A nucleosome array undergoes LLPS. A, DNA has a negatively charged phosphate backbone, while the core histone proteins are enriched with positively charged amino acids. The nucleosome is formed by electrostatic interactions between DNA and the histone octamer, which may halve the negative charge of DNA. B, A nucleosome array undergoes LLPS upon cation or histone H1 addition in vitro. C, Interphase chromatin forms a large and irregular assembly that behaves like a “liquid droplet” in the nucleus. Metaphase chromosomes are coated with Ki‐67 (orange), which serves as a surfactant
Figure 3
Figure 3
RNAs are regulatory factors for LLPS in the nucleus. A, RNA serves in the “seeding” of membraneless organelles in the nucleus. Many non–coding RNAs (ncRNAs) are localized on chromatin and recruit RNA binding proteins that drive LLPS. B, Non–specific RNAs buffer LLPS of proteins. A specific ncRNA, such as NEAT1, facilitates LLPS of the fused in sarcoma (FUS) protein, while the LLPS of FUS is repressed by an increasing concentration of non–specific RNAs. C, Single‐stranded RNAs containing repetitive sequences tend to self‐assemble through their multivalent base‐pairings
Figure 4
Figure 4
Transcription regulation by membraneless structures in the nucleus. A, A super‐enhancer is a cluster of enhancers that are bound by RNA polymerase II, transcription factors, the mediator subunit MED1 and bromodomain‐containing protein 4 (BRD4). Super‐enhancers are locally concentrated and create a microenvironment for highly active transcription. B, ELEANOR RNA cloud (green) in the nucleus (blue) in a recurrent estrogen receptor‐positive breast cancer model cell (left). ELEANORS activate a large chromatin domain containing multiple breast cancer‐related genes (right)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mao YS, Zhang B, Spector DL. Biogenesis and function of nuclear bodies. Trends Genet. 2011;27:295‐306. - PMC - PubMed
    1. Zaidi SK, Young DW, Javed A, et al. Nuclear microenvironments in biological control and cancer. Nat Rev Cancer. 2007;7:454‐463. - PubMed
    1. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62:676‐689. - PMC - PubMed
    1. Jazaeri AA. Molecular profiles of hereditary epithelial ovarian cancers and their implications for the biology of this disease. Mol Oncol. 2009;3:151‐156. - PMC - PubMed
    1. Jackson SP, Bartek J. The DNA‐damage response in human biology and disease. Nature. 2009;461:1071‐1078. - PMC - PubMed