Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is a key event in clear cell renal carcinoma (ccRCC).
• VHL inactivation leads to the activation of hypoxia-inducible transcription factors (HIFs), but VHL mutation status does not predict clinical outcome in ccRCC.
• Cancer cells utilize epigenetic modifications to enhance VHL-HIF pathway signaling for metastasis during ccRCC progression.

Purpose of the Study:

• To investigate the role of epigenetic alterations in the VHL-HIF pathway during ccRCC metastasis.
• To identify specific epigenetic mechanisms that promote metastasis in VHL-deficient ccRCC.
• To correlate the strength of VHL-HIF pathway activation with clinical outcomes in ccRCC.

Main Methods:

• Analysis of metastatic subpopulations of VHL-deficient ccRCC cells.
• Investigation of epigenetic alterations, including Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) and DNA methylation.
• Examination of the expression of VHL-HIF target genes, such as chemokine (C-X-C motif) receptor 4 (CXCR4) and cytohesin 1 interacting protein (CYTIP).

Main Results:

• A distinct epigenetically altered VHL-HIF response was identified in metastatic ccRCC.
• Loss of H3K27me3 activates HIF-driven CXCR4 expression, promoting chemotactic cell invasion.
• Loss of DNA methylation enables HIF-driven CYTIP expression, enhancing cancer cell survival against death cytokine signals.

Conclusions:

• Metastasis in ccRCC is driven by an epigenetically expanded output of the VHL-HIF pathway.
• Epigenetic modifications provide a mechanism for VHL-deficient ccRCC cells to acquire metastatic potential.
• Targeting these epigenetic alterations may offer therapeutic strategies for ccRCC metastasis.