Overexpression of promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.

BACKGROUND

Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.

RESULTS

We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) , , and in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature.

CONCLUSION

These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.