Targeting phase separation on enhancers induced by transcription factor complex formations as a new strategy for treating drug-resistant cancers

Abstract

The limited options for treating patients with drug-resistant cancers have emphasized the need to identify alternative treatment targets. Tumor cells have large super-enhancers (SEs) in the vicinity of important oncogenes for activation. The physical process of liquid-liquid phase separation (LLPS) contributes to the assembly of several membrane-less organelles in mammalian cells. Intrinsically disordered regions (IDRs) of proteins induce LLPS formation by developing condensates. It was discovered that key transcription factors (TFs) undergo LLPS in SEs. In addition, TFs play critical roles in the epigenetic and genetic regulation of cancer progression. Recently, we revealed the essential role of disease-specific TF collaboration changes in advanced prostate cancer (PC). OCT4 confers epigenetic changes by promoting complex formation with TFs, such as Forkhead box protein A1 (FOXA1), androgen receptor (AR) and Nuclear respiratory factor 1 (NRF1), inducing PC progression. It was demonstrated that TF collaboration through LLPS underlying transcriptional activation contributes to cancer aggressiveness and drug resistance. Moreover, the disruption of TF-mediated LLPS inhibited treatment-resistant PC tumor growth. Therefore, we propose that repression of TF collaborations involved in the LLPS of SEs could be a promising strategy for advanced cancer therapy. In this article, we summarize recent evidence highlighting the formation of LLPS on enhancers as a potent therapeutic target in advanced cancers.

Role of RNA binding proteins of the Drosophila behavior and human splicing (DBHS) family in health and cancer

“…Phase separation is a driving force to form molecular condensates and MLOs [ 35 , 36 ]. For example, the liquid-liquid phase separation (LLPS), a type of phase separation, plays important roles in the formation of molecular condensates with non-ordered structures.…”

A Liquid–Liquid Phase Separation-Related Index Associate with Biochemical Recurrence and Tumor Immune Environment of Prostate Cancer Patients

“…Moreover, the relevant studies continuously revealed the correlation of LLPS with tumorigenesis and tumor development [ 13 , 14 ]. Several studies had reported the importance of LLPS in PCa treatment and progression [ 15 ]. Widely recognized, the resistance to anti-androgen therapy of patients with PCa might due to the androgen receptor (AR) mutations or splice variants restoring AR signaling [ 16 ].…”