SIRT6 deficiency impairs the deacetylation and ubiquitination of UHRF1 to strengthen glycolysis and lactate secretion in bladder cancer

Aberrant interplay between epigenetic reprogramming and metabolic rewiring events contributes to bladder cancer progression and metastasis. How the deacetylase Sirtuin-6 (SIRT6) regulates glycolysis and lactate secretion in bladder cancer remains poorly defined. We thus aimed to study the biological functions of SIRT6 in bladder cancer.

Bioinformatic analysis was used to study the prognostic significance of SIRT6/UHRF1 in BLCA. Both in vitro and in vivo assays were used to determine the roles of SIRT6/UHRF1 in BLCA. Deacetylation and ubiquitin assays were performed to uncover the regulations of SIRT6-UHRF1. Measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) was used to assess glycolytic abilities.

Here, we show that protein deacetylase SIRT6 was down-regulated in BLCA, and predicts poor overall survival. SIRT6 deficiency notably enhances BLCA cell proliferation, self-renewal, and migration capacities in vitro and in vivo. Mechanistically, SIRT6 interacts with, deacetylates, and promotes UHRF1 degradation mediated by β-TrCP1. Thus, SIRT6 deficiency leads to stabilized UHRF1 and depends on UHRF1 to accelerate BLCA malignant progression. Furthermore, UHRF1 significantly increased aerobic glycolysis via activating MCT4/HK2 expressions. Down-regulated SIRT6 thus depended on UHRF1 to promote glycolysis and lactate secretion in BLCA. Targeting UHRF1 or MCT4 notably impaired the extracellular lactate accumulations in BLCA. Significantly, a specific small-molecule inhibitor (NSC232003) targeting UHRF1 substantially inhibited SIRT6-deficient BLCA progression.

Together, our study uncovered an epigenetic mechanism of the SIRT6/UHRF1 axis in driving BLCA glycolysis and lactate secretion, creating a novel vulnerability for BLCA treatment.