LncRNA LIMp27 Regulates the DNA Damage Response through p27 in p53-Defective Cancer Cells.
Ting LaSong ChenXiao Hong ZhaoShuai ZhouRan XuLiu TengYuan Yuan ZhangKaihong YeLiang XuTao GuoMuhammad Fairuz JamaluddinYu Chen FengHai Jie TangYanliang WangQin XuYue GuHuixia CaoTao LiuRick F ThorneFeng-Min ShaoYuan Yuan ZhangLei JinPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
Keyphrases
- wild type
- cell cycle arrest
- dna damage
- induced apoptosis
- cell death
- pi k akt
- dna damage response
- oxidative stress
- poor prognosis
- dna repair
- signaling pathway
- end stage renal disease
- long non coding rna
- binding protein
- chronic kidney disease
- endothelial cells
- newly diagnosed
- endoplasmic reticulum stress
- prognostic factors
- drug delivery
- cell proliferation
- radiation therapy
- combination therapy
- replacement therapy
- free survival