The Function Of Transcription Factors KLF14

Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. The Kruppel-like factors (KLFs) have received intensive investigations in human physiological and pathological processes. Recently, KLF14 has elicited attention as a master regulator of lipid metabolism, but its precise physiological role remains largely unknown.In this study, we disrupted KLF14 gene in mice, and report that KLF14 depletion causes centrosome amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of PLK4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce PLK4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated whereas PLK4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and PLK4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon carcinogenesis in mice. These results suggest that KLF14 reduction promotes PLK4-directed centrosome amplification, and as a consequence, tumor formation. Thus our findings reveal that KLF14 reduction is a new causative mechanism for centrosome amplification and chromosome instability in human cancer. On the other hand, forced expression of KLF14 leads to severe mitotic catastrophe, a promising end point in cancer treatment.Collectively, our findings identify KLF14 as a novel tumor suppressor, and highlight its potential as a potential biomarker and therapeutic target for cancer.