Targeting phase separation: a promising treatment option for hepatocellular carcinoma

Abstract

The spontaneous phenomena known as liquid-liquid phase separation (LLPS) is caused by weak interactions between substances. Under specific circumstances, macromolecules like proteins and nucleic acids can dynamically aggregate to form biomolecular condensates. This phenomenon offers a novel perspective on the intricate spatiotemporal coordination within living cells. Recent research has shown that LLPS is crucial for the initiation and progression of cancer, mainly by influencing multiple cellular activities such as metabolism, autophagy, stress responses, immune reactions, transcriptional regulation and intracellular signaling pathways, etc. Dysregulation of LLPS significantly affects the proliferation, metastasis, and therapeutic resistance of hepatocellular carcinoma (HCC) cells. Here, we introduce recent advances in understanding how LLPS regulates HCC-associated signaling pathways. Furthermore, we discuss the molecular mechanisms underlying the LLPS of oncogenic signaling molecules and its potential implication. Finally, we summarize several feasible approaches for treating HCC by targeting LLPS. These findings have the potential to establish a novel theoretical framework and therapeutic hypothesis for cancer treatment, thus providing more precise and individualized clinical strategies and significantly enhance patient prognosis and overall survival rates.

Keywords: Biomolecular condensates; Hepatocellular carcinoma; Liquid-liquid phase separation; Signaling pathway; Targeted therapy.

Fig. 1

Factors regulating liquid-liquid phase separation. A variety of factors can promote or inhibit liquid-liquid separation, including temperature, component concentration, salt concentration, chaperones, and PTM

Fig. 2

Role of LLPS in oncogenic signaling in HCC. cGAS-dsDNA condensates promote cGAMP production and innate immune signaling. Laforin-Mst1/2 condensates disrupt WW45-Mst1/2 complex and activate Yap to promote HCC development. Fetal TAK1 interacts with TAB3, forming liquid-like condensates and maintaining MAPK signaling activation to promote tumor proliferation. PrPc generates LLPS and recruits TRAF2, TAB3 and TAK1 to form a dynamic condensate that activates the NF-κB signaling pathway to accelerate tumor progression. DnaJB1-PKAcat inhibits RIα’s LLPS, disrupting the cAMP compartment and dysregulating the cAMP/PKA signaling pathway. High levels of p62 bodies activate Nrf2 signaling and accelerate cancer development. The formation of paraspeckles activates STAT3 and promotes HCC progression

Fig. 3

Prospects for HCC treatment by regulating LLPS. A Metformin disrupts the Twist1-YY1-p300 condensates, thereby decreasing the expression of miR-9 and thus inhibiting HCC progression. B Elvitegravir specifically binds to the SRC-1/YAP/TEAD condensate and hence antagonize YAP oncogenic transcriptional activity. C 2142-R8 peptide disrupts KAT8–IRF1 condensates and consequently down-regulate PD-L1 expression and enhance antitumor immunity. D Development of hydrogel scaffolds mimics the structural organization of liver by phase separation between polyethylene glycol and dextran. E CircVAMP3 interacted with CAPRIN1 and G3BP1 inhibits the translation of c-Myc through the formation of SGs to negatively regulate HCC cells proliferation and migration. F CircASH2 regulates TPM4 to alter tumor cytoskeleton for inhibiting HCC invasion and metastasis by promoting YBX1 LLPS. G GalNAc-si URB1-AS1 increases sorafenib resistance in HCC by inhibiting ferritin phase separation