Fumarate activates the IL-6/JAK/STAT3 pathway by inhibiting KDM4C-mediated H3K36me3 demethylation in FH-knockdown renal cancer cells.

Background: Fumarate is a small molecule metabolite accumulating in fumarate hydratase-deficient renal cell carcinoma (FH-RCC) cells and plays a key role in the malignant transformation. However, the underlying mechanism remains to be investiagted.

Methods: The comprehensive transcriptomic profiling of FH-knockdown cells was meticulously examined through RNA-sequencing. Differentially expressed genes were validated using qPCR, WB, and IHC. ChIP-qPCR experiments were conducted to evaluate the histones involved in the process. In vivo and in vitro studies revealed fumarate exerts an inhibitory effect on KDM4C activity. Cell proliferation and invasion assays were utilized to assess the roles of FH and KDM4C in FH-RCC tumorigenesis.

Results: We discovered that accumulated fumarate in FH-knockdown ACHN and HK-2 cells competitively binds to α-ketoglutaric acid (α-KG), effectively inhibiting the activity of the histone demethylase KDM4C and significantly increasing the level of histone 3 lysine 36 trimethylation (H3K36me3). The upregulation of H3K36me3 expression triggered the activation of the IL-6/JAK/STAT3 oncogenic signaling pathway and increased the expression of the chemokine CXCL10. Phosphorylated STAT3 (p-STAT3) further enhanced programmed cell death ligand 1 (PD-L1) expression.

Conclusions: Collectively, these findings suggest that combining immune checkpoint blockade (ICB) with a STAT3 inhibitor may hold promise for patients with fumarate hydratase-deficient renal cell carcinoma.