Abstract B010: PITAR, a <i>p</i>53 inactivating TRIM28 associated RNA, executes an alternate way of p53 inactivation
Authors: Kumar Somasundaram
Journal: Cancer Research (2024)

Abstract Much of the human genome, once considered "junk DNA," is now shown to be pervasively transcribed into thousands of long noncoding RNAs (lncRNAs). Over the last two decades, accumulated evidence implicated lncRNA in fundamental biological processes that play an essential role in several pathological conditions like cancer. Glioblastoma (GBM), the model cancer for our studies, is a grade IV glioma and is the most common and malignant primary adult brain tumor. GBM patients usually undergo surgical resection (maximal near-safe surgery) with complementary concomitant radiotherapy and Temozolomide chemotherapy followed by five cycles of Temozolomide chemotherapy. However, this treatment never leads to a cure. One primary reason for this poor prognosis is the presence of cancer stem cells (CSCs) in GBM, which can initiate a tumor and resist currently available treatments. Targeting GSCs (Glioma stem cells, CSC equivalent in glioma) holds great promise in treating this intractable cancer. The tumor suppressor protein p53 is essential for maintaining genome integrity and preventing malignant transformation. While p53 undergoes genetic alterations in significant proportions of human tumors, inactivation occurs through other genetic or epigenetic alterations in remaining tumors. Recent work from our laboratory profiled the expression of lncRNAs and mRNAs simultaneously and identified complex regulatory networks and clinically relevant lncRNAs in glioblastomas (GBMs) compared to Control brain samples. This study also identified the regulated LncRNAs in glioma stem-like cells (GSCs), equivalent to cancer stem cells (CSCs) of glioma. An integrated analysis of the above data identified several lncRNAs that are upregulated in GBM and GSCs. We believe investigating these GSC-specific lncRNAs has a high potential to understand the biology of glioma and develop novel therapeutic modalities. Here we have identified a long noncoding RNA, PITAR (p53 Inactivating TRIM28 associated RNA), as an inhibitor of p53. PITAR is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We found that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels, enhanced p53 ubiquitination, and attenuated DNA damage response. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth and promoted resistance to Temozolomide. DNA damage also activated PITAR, in addition to p53, thus creating an incoherent feedforward loop. Thus, we establish an alternate way of p53 inactivation and propose PITAR, an oncogenic Cancer/testis lncRNA, as a potential therapeutic target. Citation Format: Kumar Somasundaram. PITAR, a p53 inactivating TRIM28 associated RNA, executes an alternate way of p53 inactivation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B010.