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Transcription Factors TP63 and SOX2 in Squamous Cell Carcinoma Progression

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Key Points

  • TP63 and SOX2 cooperatively and lineage-specifically regulate the expression of CCAT1—a long noncoding RNA which is associated with multiple cancers including SCCs—through activation of its super-enhancers and promoter.
  • CCAT1 forms a protein complex with TP63 and SOX2 which then binds to the super-enhancers of EGFR to further activate two signaling pathways that ultimately trigger SCC progression.

Squamous cell carcinomas (SCCs) are malignancies arising from squamous epithelium of various organs, such as esophagus, head and neck, lung, and skin.  Previous studies demonstrated that two master transcription factors, TP63 and SOX2, effect genomic activation in SCCs. Now, researchers from the Cancer Science Institute (CSI) of Singapore at the National University of Singapore have taken a step further and identified an SCC-specific protein complex activated by TP63 and SOX2, which triggers a gene cascade that promotes SCC growth. These findings were published by Jiang et al in Nature Communications.

Further Investigation

To further investigate the roles of TP63 and SOX2 in SCCs, the team carried out epigenomic profiling of 4 different types of SCCs. Their analysis revealed that TP63 and SOX2 cooperatively and lineage-specifically regulate the expression of CCAT1—a long noncoding RNA which is associated with multiple cancers including SCCs—through activation of its super-enhancers and promoter. CCAT1 forms a protein complex with TP63 and SOX2 which then binds to the super-enhancers of EGFR to further activate two signaling pathways that ultimately trigger SCC progression.

This sequence of molecular interactions driven by TP63 and SOX2 that the team uncovered opens up an array of avenues in which SCC progression can be interfered. “By elucidating the roles of TP63 and SOX2, we not only have identified possible cancer targets but also shed light on the related pathways that will act on SCCs. Collectively, the new knowledge [may] help pave the way for innovative SCC therapies to be developed,” said H. Phillip Koeffler, MD, Senior Principal Investigator at CSI Singapore and lead researcher for this study, in a statement. 

Moving forward, the research team will look into more advanced mechanisms of the master transcription factors, TP63 and SOX2, on SCC development. Using mathematic modelling, the research team will look into the interconnected transcriptional circuit formed by these master transcription factors, as well as their interactions with other super-enhancers. This may provide new clues that can contribute to the development of novel and effective therapeutic modality for SCCs.

Disclosure: See study authors’ full disclosures at nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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