Related Experiment Video
Updated: Aug 6, 2026
Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
Published on: May 14, 2016
Celastrol's covalent strike on HK2: Breaking a metabolic-epigenetic circuit to impede bladder cancer
Tong Shi1, Chaoying Wen1, Zhaoran Wang1
1China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100029, China; Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China.
Abstract:
This study investigated how the natural compound celastrol (CEL) impedes bladder cancer (BLCA) progression by irreversibly occupying the ATP-binding pocket of hexokinase 2 (HK2). CEL binds directly to the ATP cleft of HK2, permanently inactivating its enzymatic function and consequently suppressing glycolytic flux and lactate output in tumor cells. The diminished availability of lactate leads to reduced histone lactylation-a recently recognized epigenetic mark-which in turn downregulates the expression of the RNA methyltransferase METTL3 and decreases the global N⁶-methyladenosine (m⁶A) abundance. Importantly, we revealed a self-reinforcing circuit linking HK2‑driven glycolysis, histone lactylation, and METTL3‑dependent m⁶A deposition that fuels malignant growth. By stably engaging the ATP-binding pocket of HK2, CEL dismantles this metabolic-epigenetic feed‑forward loop, a mechanism that was substantiated through in vitro and in vivo assays and an analysis of clinical samples. Collectively, these results define a pivotal metabolic-epigenetic axis in BLCA and identify CEL as an agent that concurrently blocks energy production and post-transcriptional regulation. The results of the present study underscore the promise of irreversible HK2 blockade as a novel therapeutic avenue for managing BLCA.
Insights
The natural compound celastrol (CEL) irreversibly blocks hexokinase 2 (HK2) in bladder cancer cells. This disrupts a metabolic-epigenetic loop fueling tumor growth, offering a potential new therapy.
Area of Science:
- Biochemistry
- Epigenetics
- Oncology
Background:
- Bladder cancer (BLCA) progression is often driven by metabolic reprogramming.
- Hexokinase 2 (HK2) is a key enzyme in cancer glycolysis.
- A metabolic-epigenetic axis involving histone lactylation and METTL3 influences tumor growth.
Purpose of the Study:
- To investigate the mechanism by which celastrol (CEL) inhibits BLCA.
- To elucidate the role of HK2 in a metabolic-epigenetic feedback loop in BLCA.
- To evaluate CEL as a potential therapeutic agent for BLCA.
Main Methods:
- In vitro and in vivo assays to study CEL's effect on HK2.
- Analysis of glycolysis, lactate production, histone lactylation, and METTL3 expression.
- Assessment of N⁶-methyladenosine (m⁶A) abundance.
- Examination of clinical BLCA samples.
Main Results:
- Celastrol (CEL) irreversibly binds to the ATP-binding pocket of HK2, inhibiting its function.
- CEL suppresses glycolytic flux and lactate production in BLCA cells.
- CEL treatment reduces histone lactylation, downregulates METTL3, and decreases global m⁶A levels.
- A metabolic-epigenetic feed-forward loop involving HK2, histone lactylation, and METTL3 was identified and disrupted by CEL.
Conclusions:
- Celastrol (CEL) effectively targets a critical metabolic-epigenetic axis in bladder cancer.
- Irreversible blockade of HK2 by CEL disrupts tumor cell energy production and epigenetic regulation.
- CEL shows promise as a novel therapeutic strategy for BLCA by targeting this axis.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...