PITAR , a DNA damage-inducible cancer/testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA

• Published in: eLife 2024-09, Vol.12
• Main Authors: Jana, Samarjit, Mondal, Mainak, Mahale, Sagar, Gupta, Bhavana, Prasasvi, Kaval Reddy, Kandasami, Lekha, Jha, Neha, Chowdhury, Abhishek, Santosh, Vani, Kanduri, Chandrasekhar, Somasundaram, Kumaravel
• Format: Article
• Language: English
• Subjects: Animals; Antisense RNA; Brain tumors; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Datasets; DNA; DNA Damage; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Gliomas; GSC; Humans; Ligases; long noncoding RNA; Male; Messenger RNA; Mice; mRNA; Non-coding RNA; p53; p53 Protein; PITAR; Protein Binding; Proteins; RNA Stability; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Temozolomide; Therapeutic targets; TRIM28; Tripartite Motif-Containing Protein 28 - genetics; Tripartite Motif-Containing Protein 28 - metabolism; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88256

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, ( 53 nactivating RIM28 ssociated NA), as an inhibitor of p53. is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of interaction with RNA stabilized mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated , in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a -dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by , which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose as a potential GBM therapeutic target.