LZTR1 acts as a potent tumor suppressor gene in liver cancer by safeguarding aberrant MAPK activity via posttranslational control of RAS GTPases

Hepatocellular carcinoma (HCC) ranks among the cancers with the highest rate of mortality, yet treating this carcinoma remains challenging due to late diagnosis and poor patient stratification, thereby preventing the utilization of targeted therapeutical approaches. Using human genome sequencing data, we identified frequent deleterious alterations of Leucine-zipper-like transcriptional regulator 1 (LZTR1), which plays a crucial role in regulation of RAS-like GTPases (e.g. RIT1) and downstream pathways, such as the mitogen activated protein kinase (MAPK) pathway. Using murine in vivo as well as human in vitro models, we reveal that loss of function of LZTR1 promotes tumorigenesis in vivo as well as cell growth in vitro, an effect accompanied by elevated RIT1 expression and subsequent MAPK pathway activation. Moreover, truncated forms of LZTR1 lacking domains crucial for its interaction with RAS molecules phenocopied the effect of LZTR1 loss, further suggesting that this interaction is crucial for tumor suppression. Finally, expression of mutant RIT1 proteins rendering RIT1 non-degradable by LZTR1 in murine livers resulted in liver tumorigenesis comparable to LZTR1 loss. Thus, our findings suggest that LZTR1 safeguards MAPK signaling by controlling RAS GTPases in the liver and could therefore potentially be utilized to stratify HCC patients for usage of small molecule inhibitors targeting MAPKs, which are currently only employed in other carcinomas.

Publication History

Article published online:
20 January 2025