Pharmacological inhibition of SRC-1 phase separation suppresses YAP oncogenic transcription activity

Zhu, Guangya; Xie, Jingjing; Fu, Zhenzhen; Wang, Mingliang; Zhang, Qichen; He, Hao; Chen, Zijun; Guo, Xin; Zhu, Jidong

doi:10.1038/s41422-021-00504-x

Cited by 31 publications

(26 citation statements)

References 13 publications

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“…3e ). 141 It is well known that YAP and TAZ are downstream effectors of the Hippo pathway—a tumor suppressor signaling pathway that is important for biological activities such as immune regulation, epithelial homeostasis, and tissue regeneration. 142 Therefore, aberrant YAP/TAZ-mediated transcriptional condensates may contribute to cancer-related pathophysiology.…”

Section: Liquid–liquid Phase Separationmentioning

confidence: 99%

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Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

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Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

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Section: Liquid–liquid Phase Separationmentioning

confidence: 99%

“…7h ). 141 Recent research has also shown that allosteric regulators may influence LLPS because allosteric sites in intrinsically disordered proteins can be managed to enhance signaling interactions between various mechanistic components. 299 …”

Section: Prospects Of Applying Llps In Cancer Treatmentmentioning

confidence: 99%

Liquid–liquid phase separation in tumor biology

Tong

Tang

et al. 2022

Sig Transduct Target Ther

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“…At the same time, they also used this phenomenon to inhibit viral RNA replication, which could be used to treat coronaviruses, such as SARS‐CoV‐2. [ 109 ]…”

Section: Drug Development Bases Pathological Phase Separationmentioning

confidence: 99%

Phase Separation: “The Master Key” to Deciphering the Physiological and Pathological Functions of Cells

Wei

et al. 2022

Advanced Biology

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Phase separation is a hot research field at present. It involves almost all aspects of cells and plays a significant role in cells, promising to be “a master key” in unlocking the mysteries of nature. In this review, the factors that affect phase separation are introduced, such as own component, electrostatic interaction, and chemical modification. Furthermore, the physiological roles of phase separation in cells, including molecules transport channel, gene expression and regulation, cellular division and differentiation, stress response, proteins refolding and degradation, cell connections, construction of skin barrier, and cell signals transmission, are highlighted. However, the disorder of phase separation leads to pathological condensates, which are associated with neurodegenerative diseases, tumors, and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). This relationship is considered the potential target for developing corresponded drugs and therapy. Some drugs targeting phase separation have improved meaningful, such as tankyrase, lipoamide, oligonucleotides, elvitagravir, nilotinib, CVL218, PJ34. All in all, mystery phase separation provides a new viewpoint for researchers to explore cells, and is expected to solve many unknown phenomena in nature.

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“…As mentioned above, aberrant YAP/TAZ-mediated transcriptional condensates may contribute to cancer-related pathophysiology (77)(78)(79). In lung cancer, siRNA library which contains siRNAs for 15 reported histone acetylation transferase (HAT) was used to perform a screening assay (121). Then it was found that YAP can further form YAP/TEAD/SRC-1 complexes by interacting with SRC-1 and extensively improve YAP transcriptional activity.…”

Section: Src1 In Lung Cancermentioning

confidence: 99%

“…Mechanistically, EVG can effectively inhibits the development of the SRC-1/YAP/TEAD complex formation to restrict tumor growth in a YAP-dependent manner by specifically targeting LLPS of SRC-1. Gene expression profiling revealed that EVG suppressed the expression of YAP target genes in lung cancer ( 121 ).…”

Section: Targeting Llps Is a Promising Therapeutic Strategy For Treat...mentioning

confidence: 99%

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

Takayama

Inoue

2022

Front. Oncol.

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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.

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Pharmacological inhibition of SRC-1 phase separation suppresses YAP oncogenic transcription activity

Cited by 31 publications

References 13 publications

Liquid–liquid phase separation in tumor biology

Liquid–liquid phase separation in tumor biology

Phase Separation: “The Master Key” to Deciphering the Physiological and Pathological Functions of Cells

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

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