Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer

SIMPLE SUMMARY: This study was conducted to investigate the clinical significance and prognostic value of KLF5 in a large cohort of Middle Eastern PTC patients and explore its functional role and mechanism in PTC cell lines in vitro and in vivo. We found KLF5 over-expression in PTC patient cases and this was significantly associated with aggressive clinico-pathological parameters and worse outcome. We also found a significant association between KLF5 and HIF-1α in PTC patients and cell lines. Functionally, KLF5 promoted cell growth, stemness, invasion, migration, and angiogenesis, while its inhibition reverses its action in PTC cell lines. Finally, the depletion of KLF5 regressed PTC tumor growth in nude mice. These data suggest that KLF5 may potentially be a suitable therapeutic target in PTC, and pharmacological inhibition of KLF5 might be a viable therapeutic option for the treatment of patients with an aggressive subtype of PTC. ABSTRACT: The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC.