Over 400 000 new renal cell carcinomas (RCC) are diagnosed yearly worldwide resulting in over 170 000 deaths. 80% of these are clear cell RCCs (ccRCC). Half of patients with ccRCC will develop metastases. Metastatic disease is considered incurable and current treatments are merely life prolonging, even though treatments has improved markedly during the past decade. RCC is a highly heterogeneous disease, although about 90 % ccRCC bear inactivation of the von Hippel-Lindau (VHL) tumour suppressor that leads to the aberrant activation of the oxygen sensing pathway mediated by hypoxia-inducible factor (HIF) activation. Here, we have studied the O2-sensing pathway components (HIF; prolyl hydroxylases, PHDs) co-operation with post-translational protein modifying regulators, in particular the SUMOylation pathway in RCC progression.

Several RCC cell lines have been used to study molecular mechanisms and responses to drugs targeting O2-sensing and SUMOylation pathways using monolayer and three-dimensional (3D) cultures. Moreover, prospectively collected nephrectomy material (iCAN flagship biobank project) and cancer tissue material from metastatic RCC patients (PROExMET study) have been used to do ex vivo drug screenings in monolayer and organoid cultures. Knockdown of the O2-sensing and SUMOylation pathway components with siRNAs in 3D RCC cell culture assays have been used to study the importance of each pathway component on RCC cell growth and their effect on the transcriptional landscape to reveal novel druggable targets in RCC.

Our data show that inhibition of global SUMOylation with TAK-981 efficiently reduces growth of RCC cells in monolayer and 3D cultures in several RCC cell lines and ex vivo patient samples, indicating that SUMOylation controls cancer growth in RCC. Preliminary data further suggests that inhibition of SUMOylation with TAK-981 may have synergistic effects with drugs targeting the O2-sensing pathway components. Mechanistically, TAK-981 treatment may downregulate HIF1 expression levels. No major changes on global SUMOylation levels were observed in RCC cells upon hypoxia.

Our results suggest that i) there is a functional crosstalk between SUMOylation and O2-sensing pathways in RCC and that ii) inhibition of global SUMOylation may have therapeutic potential in RCC.

We thank Misvik Biology Oy for monolayer drug screenings, Dr. Sakari Vanharanta (University of Helsinki) for providing valuable cell lines, Saiganesh Sriraman for valuable discussions and iCANDOC doctoral program for financial support.