Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.

Min Li, Zheng Wang, Jingjing Tao, Hongfei Jiang, Huang Yang, Dong Guo, Hong Zhao, Xuxiao He, Shudi Luo, Xiaoming Jiang, Li Yuan, Liwei Xiao, Haiyan He, Rilei Yu, Jing Fang, Tingbo Liang, Zhengwei Mao, Daqian Xu, Zhimin Lu

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. · pubmed

Paper

Abstract

Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition of telomerase activity, reduction in telomere lengths, enhanced senescence and suppressed tumor cell proliferation and growth in mice. Lipid nanoparticle-mediated delivery of FBP1 mRNA inhibits liver tumor growth. Additionally, FBP1 expression levels inversely correlate with TERT pSer227 levels in renal and hepatocellular carcinoma specimens and with poor prognosis of the patients. These findings demonstrate that FBP1 governs cell immortality through its protein phosphatase activity and uncover a unique telomerase regulation in tumor cells attributed to the downregulation or deficiency of FBP1 expression.

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Research summary

The paper explores the regulation of telomerase activity through the interaction of FBP1 and TERT, which is relevant to the mechanisms of cellular aging and immortality. While it provides solid insights into tumor suppression and the role of telomerase in cancer, the findings primarily focus on cancer biology rather than directly addressing the root causes of aging or lifespan extension. Thus, while it contributes to the understanding of aging-related processes, its impact is limited in the broader context of longevity research.

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