Importantly, in addition to its canonical function in lipid metabolic process, our study further established two more intriguing SCC-specific roles of SREBF1: (i) SREBF1, TP63, and KLF5 co-activate the transcription of each other, forming a feedback co-regulatory loop; (ii) SREBF1, TP63, and KLF5 cooperatively regulate the transcription of hundreds of genes specifically in SCC cells, activating cancer-associated signaling pathways such as ErbB and mTOR signaling cascades. This evidence concerns the gene EGFR and cancer.