The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response

The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response

Abstract Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions...

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Main Authors: Mingming Sun, Qi Yan, Xinru Zhai, Xintong Dai, Chenxin Yang, Huifang Zhao, Sizhen Lai, Jiyan Wang, Lian Li, Zhen Li, Yanping Li, Taoyuan Wang, Tao He, Jun Xue, Zhenghu Jia, Chunze Zhang, Shuai Zhang, Changliang Shan
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Journal of Experimental & Clinical Cancer Research
Subjects:
Colorectal cancer (CRC)
6-phosphogluconate dehydrogenase (6PGD)
Non-metabolic activity
Proliferation
Metastasis
Online Access:https://doi.org/10.1186/s13046-025-03450-3
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Summary:Abstract Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m6A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity.
ISSN:1756-9966

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