Isoform‐specific effects of transcription factor TCFL5 on the pluripotency‐related genes SOX2 and KLF4 in colorectal cancer development

• Published in: Molecular oncology 2022-05, Vol.16 (9), p.1876-1890
• Main Authors: Galán‐Martínez, Javier, Stamatakis, Konstantinos, Sánchez‐Gómez, Inés, Vázquez‐Cuesta, Silvia, Gironés, Núria, Fresno, Manuel
• Format: Article
• Language: English
• Subjects: Analysis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cancer; Cancer therapies; Cell migration; Cell Proliferation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; CRISPR; Epidermal growth factor; Fibroblasts; Gene expression; Genes; Genetic aspects; Humans; Isoforms; Kinases; KLF4; KLF4 protein; Kruppel-Like Factor 4 - metabolism; Malignancy; Microscopy; Plasmids; Pluripotency; Promoter Regions, Genetic; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; RNA; RNA, Messenger - genetics; SOX2; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Spheroids; TCFL5; Transcription factors; Transcription Factors - metabolism; Tumors; Wound healing
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13085

Colorectal cancer (CRC) is a very common life‐threatening malignancy. Transcription factor‐like 5 (TCFL5) has been suggested to be involved in CRC. Here, we describe the expression of four alternative transcripts of TCFL5 and their relevance in CRC. Complete deletion of all isoforms drastically decreased pro‐tumoural properties such as spheroids formation and in vivo tumour growth, although increased migration in CRC cell lines. Overexpression of the two main isoforms, TCFL5_E8 and CHA, had opposite effects: TCFL5_E8 reduced proliferation and spheroids formation, while CHA increased them. TCFL5_E8 reduced in vivo tumour formation, while CHA had no effect. In addition, TCFL5_E8 and CHA have different roles in the regulation of the pluripotency‐related genes SOX2 and KLF4. Both isoforms bind directly to their promoters; however, TCFL5_E8 induced SOX2 and reduced KLF4 mRNA levels, whereas CHA did the opposite. Together, our results show that TCFL5 plays an important role in the development of CRC, being however isoform‐specific. This work also points to the need to analyse separately TCFL5 isoforms in cancer, due to their different and opposite functions. In this study, the authors identify four isoforms of TCFL5 in colorectal cancer, each with strikingly different properties. Complete deletion of the TCFL5 locus reduced tumour cell proliferation and spheroid formation, but increased migration. However, whereas overexpression of the TCFL5_E8 isoform reduced proliferation and spheroid formation, overexpression of the CHA isoform increased them. In addition, CHA and TCFL5_E8 bound to the SOX2 and KLF4 promoters directly, controlling their transcription.