CUX1 in liver cancer: experimental study in hypoxia model

Background: CUX1 (CUTL1) is a transcription factor able to promote the expression of several genes implicated in cellular proliferation, differentiation and demise. In normal adult cells, it preferentially favors the expression of proapoptotic genes. Its aberrant expression in tumor turns its role as foe. It favors the expression of oncogenes and survival factors, especially in stress condition, thus supporting tumorigenesis. Here, we show CUX1 activity during hypoxia in liver cancer cells.

Materials/Methods: CUX1was knocked down and its targets were analysed by RT-qPCR in HepG2 and Hep3B cells under hypoxic and/or normal culture condition. The hypoxia condition was established by 24h treatment with 150µM CoCl2 or with 0.5% O2 atmosphere.

Results: Hypoxia determined the up-regulation of HIF1-alpha (Hypoxia inducible factor1-alpha) and a stable or up-regulated expression of its inhibitor FIH-1 (SLC2A1) up to 24h prolonged hypoxia. VEGFA was significantly overexpressed. Knock-down of CUX1 determined a significant down-regulation of HIF-1alpha, FIH-1 and VEGFA. Interestingly, the expression of CDKN1A was only attenuated after CUX1 knock down and hypoxic stress.

Conclusions: CUX1 exerts an oncogenic role in liver cancer by sustaining the survival mechanism beyond hypoxia. CUX1 silencing results in suppression of the hypoxia inducible factor and its target VEGFA causing a block of cell cycle in liver cancer cells modulated by the stable expression of CDKN1A.

Corresponding author: Di Fazio, Pietro

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