Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.
Min LiZheng WangJingjing TaoHongfei JiangHuang YangDong GuoHong ZhaoXuxiao HeShudi LuoXiaoming JiangLi YuanLiwei XiaoHaiyan HeRilei YuJing FangJianpeng ShengZheng-Wei MaoDaqian XuZhimin LuPublished in: Nature chemical biology (2024)
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.
Keyphrases
- poor prognosis
- long non coding rna
- cell proliferation
- induced apoptosis
- binding protein
- papillary thyroid
- cell cycle arrest
- end stage renal disease
- newly diagnosed
- oxidative stress
- ejection fraction
- signaling pathway
- single cell
- squamous cell
- dna damage
- endoplasmic reticulum stress
- transcription factor
- cell cycle
- endothelial cells
- squamous cell carcinoma
- adipose tissue
- pi k akt
- fatty acid
- prognostic factors
- stress induced
- amino acid
- young adults
- childhood cancer
- metabolic syndrome
- patient reported
- fine needle aspiration