The Hippo pathway in clear cell renal cell carcinoma (ccRCC): a nexus with the VHL disruption?

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) represents 70% of kidney cancers, with 20-50% recurrence risk after surgery. Despite therapeutic advances, no reliable biomarkers have been identified for patient stratification or treatment response prediction. While VHL gene alterations are well-established in ccRCC pathogenesis, the role of the Hippo pathway remains underexplored despite ample evidence of its involvement. OBJECTIVE: This review synthesizes current knowledge on Hippo pathway alterations in ccRCC and examines its crosstalk with the VHL/HIF axis, identifying potential biomarkers and therapeutic targets. STRATEGY: We comprehensively analyzed literature on Hippo pathway components in ccRCC, focusing on molecular mechanisms, clinical correlations, and interactions with VHL signaling. RESULTS: Multiple Hippo pathway alterations characterize ccRCC: RASSF1A hypermethylation, NF2 mutations (particularly in aggressive variants), SAV1 downregulation associated with 14q loss, and LATS1/2 methylation-mediated inactivation. These changes result in YAP/TAZ nuclear accumulation and oncogenic transcription. Importantly, chromosome 3p loss simultaneously disrupts both VHL and RASSF1, creating a unique double-hit scenario. The VHL-Hippo crosstalk operates through multiple mechanisms: HIF-induced GPRC5A and VEGFR signaling inhibit LATS1/2 phosphorylation, promoting YAP/TAZ activation, while active YAP/TAZ enhances pro-angiogenic gene transcription, amplifying hypoxic responses. Low expression of RASSF1A, SAV1, and LATS1/2, coupled with high YAP/TAZ activity, correlates with advanced tumor stage, higher grade, and poorer survival. CONCLUSIONS: The Hippo pathway represents a critical yet underappreciated dimension of ccRCC biology, offering promising biomarkers for risk stratification and novel therapeutic targets. The Hippo-VHL nexus presents multiple intervention points that could enhance current treatment.