A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to suppress tumorigenesis
Transcriptional factors (TFs) act as key determinants of cell death and survival by differentially modulating gene expression. Here, we identified many TFs, including TEAD4, that form condensates in stressed cells. In contrast to YAP-induced transcription-activating condensates of TEAD4, we found that co-factors such as VGLL4 and RFXANK alternatively induced repressive TEAD4 condensates to trigger cell death upon glucose starvation. Focusing on VGLL4, we demonstrated that heterotypic interactions between TEAD4 and VGLL4 favor the oligomerization and assembly of large TEAD4 condensates with a nonclassical inhibitory function, i.e., causing DNA/chromatin to be aggregated and entangled, which eventually impede gene expression. Based on these findings, we engineered a peptide derived from the TEAD4-binding motif of VGLL4 to selectively induce TEAD4 repressive condensation. This "glue" peptide displayed a strong antitumor effect in genetic and xenograft mouse models of gastric cancer via inhibition of TEAD4-related gene transcription. This new type of repressive TF phase separation exemplifies how cofactors can orchestrate opposite functions of a given TF, and offers potential new antitumor strategies via artificial induction of repressive condensation.
Authors
- Chuanchuan Li (ORCID: https://orcid.org/0000-0001-5891-6335)
- Dan Ye (ORCID: https://orcid.org/0000-0003-4848-0501)
- Hanying Zhu
- Y. F. Han (ORCID: https://orcid.org/0000-0002-7084-8424)
- Zhaocai Zhou (ORCID: https://orcid.org/0000-0002-5441-3922)
- Zhifa Cao (ORCID: https://orcid.org/0000-0003-0496-5179)
- Yang Tang (ORCID: https://orcid.org/0000-0001-5490-3385)
- Ge‐Min Fang (ORCID: https://orcid.org/0000-0003-4149-4062)
- Xinru Zhang (ORCID: https://orcid.org/0000-0003-0643-390X)
- Hui Zhang (ORCID: https://orcid.org/0009-0000-7666-3052)
- Fan Chen (ORCID: https://orcid.org/0000-0002-4921-7484)
- Wenjia Wang (ORCID: https://orcid.org/0000-0002-2892-6214)
- Liwei An (ORCID: https://orcid.org/0000-0003-4514-5476)
- Shi Jiao (ORCID: https://orcid.org/0000-0003-3591-8973)
- Fenghua Guo (ORCID: https://orcid.org/0000-0003-2885-4430)
- Yanni Zhang (ORCID: https://orcid.org/0000-0003-2856-3182)
- Yun Zhao (ORCID: https://orcid.org/0000-0002-7807-6094)
- Lijie Tan (ORCID: https://orcid.org/0009-0006-3137-199X)
- Junyi Ju (ORCID: https://orcid.org/0000-0001-5864-0025)
Institutions
- Tongji University (CN)
- Shanghai Medical College of Fudan University (CN)
- Anhui University (CN)
- Fudan University (CN)
- Hefei Institutes of Physical Science (CN)
- Ministry of Education (KR)
- Center for Excellence in Molecular Cell Science (CN)
- Zhongshan Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- Huashan Hospital (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s44318-024-00257-4
- Citations
- 8
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 2.61
Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China