2,3-Bisphosphoglycerate mutase (BPGM) defines a stress-resilient metabolic state in clear cell renal cell carcinoma

Methods

We investigated the role of the glycolytic enzyme 2,3-bisphosphoglycerate mutase (BPGM) in ccRCC using human tumor specimens, siRNA-mediated gene silencing, functional cell-based assays, and transcriptomic profiling. Epigenetic stress was induced using the histone deacetylase inhibitor Vorinostat as a tool compound. Results: BPGM expression was consistently elevated in human ccRCC tissue compared with adjacent normal kidney. ccRCC A498 cells exhibited high basal BPGM levels and limited sensitivity to Vorinostat, whereas BPGM depletion increased cellular stress responses and reduced proliferative capacity.

Despite inducing similar phenotypic outcomes, BPGM silencing and Vorinostat treatment triggered markedly distinct transcriptional programs. While HDAC inhibition caused broad, unspecific gene deregulation, BPGM loss elicited a focused stress-associated response, including activation of unfolded protein response and ferroptosis-related gene signatures. Conclusions: Our data identify BPGM as a determinant of metabolic stress resilience in ccRCC.

By shaping selective transcriptional stress responses rather than global epigenetic reprogramming, BPGM may contribute to the intrinsic robustness of renal cancer cells. Targeting metabolic stress adaptation pathways may therefore complement epigenetic strategies in ccRCC.