KLF5 (Krüppel-like factor 5) plays critical roles in normal and cancer cell proliferation through modulating cell cycle progression. In this study, we demonstrated that curcumin targeted KLF5 by promoting its proteasome degradation, but not by inhibiting its transcription in bladder cancer cells. We also demonstrated that lentivirus-based knockdown of KLF5 inhibited cancer cell growth, while over-expression of a Flag-tagged KLF5 could partially reverse the effects of curcumin on cell growth and cyclin D1 expression. Furthermore, we found that curcumin could down-regulate the expression of Hippo pathway effectors, YAP and TAZ, which have been reported to protect KLF5 protein from degradation. Indeed, knockdown of YAP by small interfering RNA caused the attenuation of KLF5 protein, but not KLF5 mRNA, which was reversed by co-incubation with proteasome inhibitor. A xenograft assay in nude mice finally proved the potent inhibitory effects of curcumin on tumor growth and the pro-proliferative YAP/TAZ/KLF5/cyclin D1 axis. Thus, our data indicates that curcumin promotes KLF5 proteasome-dependent degradation through targeting YAP/TAZ in bladder cancer cells and also suggests the therapeutic potential of curcumin in the treatment of bladder cancer.

H19 is a long noncoding RNA differentially expressed in many tumors and participates in tumorigenesis. This study aimed to investigate the expression and function of H19 in pancreatic ductal adenocarcinoma (PDAC). Pure malignant cells were isolated from frozen sections of 25 PDAC cases by laser captured microdessection, and H19 expression level was detected by qRT-PCR. Knockdown and overexpression were employed to manipulate H19 levels in pancreatic cancer cells, then cell viability, proliferation, apoptosis and cell cycle, and the growth of xenografts were evaluated. E2F-1 levels in PDAC tissues were detected by Western blot and immunohistochemical analysis. We found that H19 was overexpressed in PDAC tissues and correlated to histological grade of PDAC. Knockdown of H19 in T3M4 and PANC-1 cells with high H19 endogenous level suppressed cell viability, proliferation and tumor growth, while H19 overexpression in COLO357 and CAPAN-1 with low H19 endogenous level enhanced cell viability, proliferation and tumor growth. Knockdown of H19 led to G0/G1 arrest, accompanied by decreased levels of E2F-1 and its downstream targets. E2F-1 was overexpressed in PDAC tissues with possible correlation with H19 expression level. In conclusion, H19 is overexpressed and plays oncogenic role in PDAC through promoting cancer cell proliferation via the upregulation of E2F-1.

Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription