Biomolecular condensates in cancer biology

Abstract

Understanding the characteristics of cancer cells is essential for the development of improved diagnosis and therapeutics. From a gene regulation perspective, the super-enhancer concept has been introduced to systematically understand the molecular mechanisms underlying the identities of various cell types and has been extended to the analysis of cancer cells and cancer genome alterations. In addition, several characteristic features of super-enhancers have led to the recognition of the link between gene regulation and biomolecular condensates, which is often mediated by liquid-liquid phase separation. Several lines of evidence have suggested molecular and biophysical principles and their alterations in cancer cells, which are particularly associated with gene regulation and cell signaling (" transcriptional" and "signaling" condensates). These findings collectively suggest that the modification of biomolecular condensates represents an important mechanism by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression. The condensate model also provides the molecular basis of the vulnerability of cancer cells to transcriptional perturbation and further suggests the possibility of therapeutic targeting of condensates. This review summarizes recent findings regarding the relationships between super-enhancers and biomolecular condensate models, multiple scenarios of condensate alterations in cancers, and the potential of the condensate model for therapeutic development.

Keywords: biomolecular condensate; cancer; intrinsically disordered region; liquid-liquid phase separation; super-enhancer.

FIGURE 1

Super‐enhancer, miRNA regulation, and cancer biology. A, Definition of super‐enhancers. B, Impacts of super‐enhancers on miRNA expression and function. Super‐enhancers drive a small subset of cell type‐specific miRNAs that are highly abundant in the relevant cell types and mediate potent target gene repression. C, Cancer hallmark traits and SE‐miRNAs with SE loss or gain in cancer cells. B and C are modified from our previous report

FIGURE 2

The transcriptional BRD4 condensate model: a link between super‐enhancer and phase separation

FIGURE 3

Alterations in transcriptional condensates and other condensates in the nuclei of cancer cells

FIGURE 4

Alterations in signaling condensates and other cytoplasmic condensates in cancer cells