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

Abstract

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