Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2

Abstract

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

Keywords

ALDOB / kidney cancer / cell proliferation

References

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Acknowledgments

This work was financially supported by grants from the National Natural Science Foundation of China (Nos. 82002683 and 81902569).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0947-9 and is accessible for authorized users.

Compliance with ethical guidelines

Mingyue Tan, Qi Pan, Qi Wu, Jianfa Li, and Jun Wang declare that they have no conflicts of interest. All procedures were performed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Declaration of Helsinki of 1975 and its revision in 2000 (5). All procedures were approved by the Institutional Review Board at the authors’ institutions (2020SQ192). Informed consent was obtained from all patients for inclusion in the study. All institutional and national guidelines for the care and use of laboratory animals were followed. All animal experiments were conducted using protocols approved by the Institutional Animal Care and Use Committee of Shanghai General Hospital (2021AWS0154, 2022AW006).

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