The yes-associated protein target gene U2AF homology motif kinase 1 facilitates tumor initiation and progression in liver cancer

Background:

Activation of the transcriptional co-activator yes-associated protein (YAP) induces hepatomegaly and eventually tumor formation in vivo. In humans YAP overexpression in about 60% of hepatocellular carcinoma (HCC) is associated with poor patient survival as well as early tumor recurrence. Very recent data illustrate that YAP induces liver tumor formation through the induction of chromosomal instability (CIN; Weiler et al., 2017 Gastroenterology). However, the functionally relevant downstream effectors of this strong oncogene have not been described in detail.

Methods and Results:

In order to identify key downstream targets, transcriptome analysis after siRNA-mediated siRNA YAP inhibition was performed. We identified the gene U2AF homology motif kinase 1 (UHMK1), which was positively regulated by YAP at the mRNA and protein levels in different HCC cell lines as well as in transgenic mice expressing inducible and constitutively active YAP. Indeed, chromatin immunoprecipitation (ChIP) experiments revealed physical binding of YAP and the transcription factor FOXM1 within the promoter of the UHMK1 gene. Gene silencing analyses showed that UHMK1 overexpression rescued cell viability after simultaneous inhibition of YAP illustrating that it partly facilitates YAP biology. Additionally, expression profiling after siRNA-mediated UHMK1 revealed that 40% of the so-called CIN70 signature, which defines cancer patients with CIN and poor clinical outcome, were regulated (e.g., MCM2, AURKB, MAD2L1, NEK2; Weiler et al., 2017, Gastroenterology; Carter et al., 2006, Nat Gen). Importantly, the hydrodynamic gene delivery of UHMK1 in conjunction with c-MYC in mice drastically fostered liver tumor development within 6 weeks. Lastly, tissue micro-array analysis illustrated a significant correlation between nuclear YAP enrichment and UHMK1 overexpression in human HCC tissues.

Conclusions:

we here identified the kinase UHMK1 as novel YAP/FOXM1 target genes. UHMK1 represents an oncogene involved in the induction of CIN and might serve as novel therapeutic target structure in a subgroup of HCC patients with YAP activation.

References:

[1] Carter SL, et al., A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006;38:1043 – 1048.

[2] Weiler SME, et al., Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology 2017;152:2037 – 2051 e2022.