Scientists shed light on the roles of transcription factors, TP63 and SOX2, in squamous cell carcinoma

Squamous cell carcinomas (SCCs) are aggressive malignant tumors resulting from the squamous epithelium of various organs, such as the esophagus, head and neck, lungs, and skin. Previous studies have shown that two major transcription factors, TP63 and SOX2, affect genomic activation in SCCs. Researchers from the Singapore Institute of Cancer Sciences (CSI Singapore) of the National University of Singapore have taken an additional step by identifying a TP63 and SOX2-activated SCC-specific protein complex that triggers a cascade of genes that promote the growth of SCC.

The results of the study were published in the prestigious scientific journal Nature Communications in September 2018.

Despite major advances in cancer research, scientists do not fully understand the development and growth of CSCs and no effective targeted treatment has been developed for the disease. CSI Singapore researchers undertook this study in collaboration with Cedars-Sinai Medical Center in Los Angeles, USA, to better understand the biology of CCS.

To further investigate the roles of TP63 and SOX2 in CHCs, the team performed epigenomic profiling of 4 different types of SCC. Their analysis revealed that TP63 and SOX2 cooperatively and specifically regulated the CCAT1 line, a long non-coding RNA associated with several cancers, including SCCs, by the activation of its super-amplifiers and its promoter. CCAT1 forms a protein complex with TP63 and SOX2 which then binds to EGFR super-amplifiers to further activate two signaling pathways that ultimately trigger the progression of SCC.

This sequence of molecular interactions driven by the TP63 and SOX2 that the team has uncovered opens up many opportunities to interfere in the progression of CCS. "By elucidating the roles of TP63 and SOX2, we have not only identified the potential cancer targets, but also illuminated the associated pathways that will affect the CCS, and together this new knowledge will help pave the way for the development of treatments. CCS, "said Professor H Phillip Koeffler, principal investigator at CSI Singapore and principal investigator for this study.

In the future, the research team will look at more advanced mechanisms of major transcription factors, TP63 and SOX2, on the development of SCCs. With the help of a mathematical modeling, the research team will examine the interconnected transcription circuit formed by these major transcription factors, as well as their interactions with other super-amplifiers. This could provide new clues that can contribute to the development of new and effective therapeutic modalities for CHCs.