CHIP/STUB1 suppresses colorectal tumorigenesis through ubiquitin-mediated degradation of LDHA and inhibition of glycolysis.

BACKGROUND: The E3 ubiquitin ligase CHIP/STUB1 is a known tumor suppressor in colorectal cancer (CRC) and other malignancies, but its mechanistic role in metabolic reprogramming remains elusive. This study aimed to elucidate whether CHIP regulates glycolysis in CRC through targeting key metabolic enzymes.
METHODS: Lentiviral systems were employed to generate SW480 and DLD1 cells with stable CHIP overexpression or knockout. These cells were subsequently assessed for proliferation, colony formation, and tumorigenic capacity in subcutaneous xenograft models. Lactate production, LDH activity, ATP levels, and histone lactylation were measured in CRC cells with altered CHIP expression. Mechanistically, Western blot, cycloheximide chase, immunoprecipitation, pull-down, and ubiquitination assays were conducted to dissect the underlying molecular events. Rescue experiments were finally performed both in vivo and in vitro to validate the functional relevance of this regulatory axis in CRC.
RESULTS: CHIP overexpression suppressed glycolysis and markedly inhibited CRC proliferation and tumorigenesis in vivo and in vitro. Mechanistically, CHIP directly bound LDHA via its TPR domain and promoted K48-linked polyubiquitination and proteasomal degradation of LDHA. This CHIP-mediated LDHA degradation reduced lactate production and subsequently decreased histone H3 lysine 18 lactylation (H3K18la), leading to transcriptional repression of cell cycle-related genes.
CONCLUSION: This work identifies LDHA as a substrate of CHIP and demonstrates that CHIP acts as a critical negative regulator of the Warburg effect in CRC. The CHIP-LDHA axis thus couples metabolic with epigenetic reprogramming and represents a potential therapeutic target.