Also published on EurekAlert! (https://www.eurekalert.org/news-releases/1140703)
When living organisms face acute energy deficiency, they must urgently enhance their energy supply to survive. Glycolysis is one of the most ancient and central energy-generating pathways in life. For a long time, although post-translational modifications (PTMs) of metabolic enzymes have been known to regulate their catalytic activities, the molecular mechanisms underlying how cells coordinate distinct PTMs during an energy crisis to prevent key enzymes from being degraded and maintain sustained, high-output energy production have remained largely unexplored.
To address this challenge, a marine shellfish research team from the Institute of Oceanology of the Chinese Academy of Sciences (IOCAS) has uncovered an ancient energy-sensing signaling cascade, termed the KAT2/HDACIIa–PGK–ALDO axis. By orchestrating a sophisticated "dual degradation inhibition" mechanism on key glycolytic enzymes (phosphoglycerate kinase (PGK) and aldolase (ALDO)), this axis stabilizes and hyperactivates both enzymes to meet cellular energy demands. Published in PNAS, these findings explain the divergence in thermal tolerance among intertidal oysters while revealing how human lung adenocarcinoma hijacks this ancient axis to drive malignant proliferation.
Integrating multi-omics data, gene editing, and biochemical functional assays, the research team discovered that under energy stress, the balance between the acetyltransferase KAT2 and the deacetylase HDACIIa shifts to promote the acetylation of PGK. This modification shields PGK from ubiquitin–proteasomal degradation while strengthening its interaction with ALDO.
In turn, stabilized PGK exerts a non-canonical protein kinase activity to directly phosphorylate ALDO, simultaneously boosting its catalytic efficiency and suppressing its chaperone-mediated autophagic–lysosomal degradation (CMA). By concurrently shutting down both the proteasome and autolysosome degradation routes, this cascade achieves a potent "stabilization-plus-activation" effect, thereby amplifying glycolytic flux to ensure cell survival.
Besides, sessile oysters in the intertidal zone regularly endure severe heat, aerial exposure, and hypoxia, exhibiting metabolic reprogramming toward aerobic glycolysis that closely mirrors the "Warburg effect" in human tumors. Building upon this evolutionary parallel, the team further demonstrated that human lung cancer cells "hijack" this ancient stress-response axis—upregulating KAT2A and downregulating HDAC5 to drive persistent hyperacetylation of PGK1-K75 and hyperphosphorylation of ALDOA-S272, which directly fuels malignant proliferation and metastasis.
"The hypoxia and energy crises endured daily by intertidal oysters remarkably mirror the human tumor microenvironment", said Dr. WANG Chaogang, first author of the study. "Their extraordinary metabolic tolerance and adaptability make them a potential unconventional model organism to decipher the fundamental principles of tumor metabolism."
"Our study bridges marine evolutionary adaptation with human cancer metabolism," said Prof. LI Li, corresponding author of the study. Hundreds of millions of years of evolution in the harsh intertidal environment have endowed oysters with an ingenious metabolic defense system. This study not only elucidates the thermal adaptation strategies of marine invertebrates in response to climate warming from an evolutionary biology perspective, but also unveils promising therapeutic targets for the clinical diagnosis and treatment of human malignancies.
The metazoan-conserved KAT2/HDACIIa–PGK–ALDO axis inhibits dual protein degradation systems to enhance glycolysis, linking oyster thermal tolerance to cancer progression. (Image by IOCAS)
(Text by WANG Chaogang)
Media Contact:
ZHANG Yiyi
Institute of Oceanology
E-mail: zhangyiyi@qdio.ac.cn
(Editor: ZHANG Yiyi)