Identification and Characterization of PITAR, a DNA Damage-Inducible Long Noncoding RNA that Inhibits p53 by Stabilizing TRIM28 mRNA in Glioblastoma

Conceitos essenciais

PITAR, a long noncoding RNA, inhibits p53 by binding and stabilizing TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, thereby promoting p53 ubiquitination and degradation.

Resumo

The study identified a long noncoding RNA called PITAR (p53 Inactivating TRIM28 associated RNA) that is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSCs). PITAR was found to be a cancer/testis lncRNA with a primarily nuclear localization.

Key highlights:

• PITAR silencing inhibited glioma cell proliferation, colony formation, and induced cell cycle arrest and apoptosis, while also sensitizing cells to DNA-damaging agents.
• PITAR interacts with and stabilizes TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase. This interaction increases TRIM28 protein levels and promotes ubiquitination-mediated degradation of p53.
• DNA damage activates PITAR in a p53-independent manner, creating an incoherent feedforward loop to inhibit the p53-mediated DNA damage response.
• PITAR silencing inhibited glioma tumor growth in vivo, while its overexpression promoted tumor growth and conferred resistance to temozolomide chemotherapy in a TRIM28-dependent manner.
• The study proposes PITAR as a potential therapeutic target for GBM, especially in tumors with wild-type p53.

Estatísticas

PITAR is significantly upregulated in multiple GBM cohorts and patient-derived GSCs compared to normal brain and differentiated glioma cells.
PITAR silencing reduced cell proliferation, viable cell count, colony formation, and induced cell cycle arrest and apoptosis in glioma cells.
PITAR silencing sensitized glioma cells to DNA-damaging agents like adriamycin and temozolomide.
PITAR overexpression promoted glioma tumor growth and conferred resistance to temozolomide chemotherapy.

Citações

"PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC)."
"PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination."
"DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53."

Principais Insights Extraídos De

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

by Jana,S., Mon... às www.biorxiv.org 04-12-2023

https://www.biorxiv.org/content/10.1101/2023.04.11.536370v2

Perguntas Mais Profundas

How might the insights from this study on PITAR's regulation of p53 through TRIM28 be leveraged to develop novel combination therapies for glioblastoma?

The study's findings on PITAR's role in inhibiting p53 through its interaction with TRIM28 mRNA provide a promising avenue for developing novel combination therapies for glioblastoma. One potential approach could involve targeting the PITAR-TRIM28 interaction to restore p53 function and enhance the tumor-suppressive effects of p53 in glioblastoma cells. This could be achieved through the development of small molecules or therapeutic agents that disrupt the binding between PITAR and TRIM28, thereby preventing TRIM28-mediated ubiquitination and degradation of p53. By restoring p53 activity, these therapies could potentially inhibit tumor growth and sensitize glioblastoma cells to existing treatments such as chemotherapy and radiation therapy.
Another strategy could involve targeting downstream effectors of the PITAR-TRIM28 axis that contribute to glioblastoma progression. By identifying key signaling pathways or proteins regulated by PITAR and TRIM28, novel combination therapies could be designed to target multiple components of the oncogenic network in glioblastoma. This multi-targeted approach could enhance treatment efficacy and overcome resistance mechanisms that often limit the effectiveness of current therapies.

How might the insights from this study on PITAR's regulation of p53 through TRIM28 be leveraged to develop novel combination therapies for glioblastoma?

In addition to its role in regulating p53 through TRIM28, PITAR may be involved in regulating other cellular pathways and processes beyond its effects on p53 and TRIM28. Given the diverse functions of long noncoding RNAs (lncRNAs) in cellular processes, it is likely that PITAR has additional roles in glioblastoma pathogenesis.
One potential pathway that PITAR may be involved in is the regulation of cell cycle progression and proliferation. As demonstrated in the study, PITAR silencing inhibited cell proliferation and colony formation in glioblastoma cells, suggesting a role in promoting cell growth. By further investigating the molecular mechanisms by which PITAR influences cell cycle progression, novel therapeutic targets could be identified to disrupt the pro-tumorigenic effects of PITAR in glioblastoma.
Moreover, PITAR may also play a role in modulating DNA damage response pathways beyond its interaction with TRIM28 and p53. Given that PITAR is induced by DNA damage in a p53-independent manner, it is possible that PITAR contributes to the regulation of DNA repair mechanisms or cell survival pathways in response to genotoxic stress. Understanding the full spectrum of pathways regulated by PITAR could uncover new therapeutic opportunities for targeting glioblastoma.

Could the cancer/testis expression profile of PITAR be exploited for the development of targeted immunotherapies for glioblastoma?

The cancer/testis expression profile of PITAR, characterized by its high expression in glioblastoma and testis but not in normal tissues, presents a unique opportunity for the development of targeted immunotherapies for glioblastoma. Cancer/testis antigens, including lncRNAs like PITAR, are attractive targets for immunotherapy due to their tumor-specific expression and immunogenicity.
One potential strategy could involve leveraging the tumor-specific expression of PITAR to design personalized immunotherapies that target PITAR-expressing glioblastoma cells. This could be achieved through the development of vaccines or adoptive cell therapies that target PITAR-expressing cells, leading to targeted immune responses against glioblastoma. By harnessing the immune system's ability to recognize and eliminate tumor cells expressing PITAR, these immunotherapies could offer a more precise and effective treatment approach for glioblastoma.
Furthermore, the cancer/testis expression profile of PITAR could also be exploited for the development of chimeric antigen receptor (CAR) T cell therapies specifically designed to target PITAR-expressing glioblastoma cells. By engineering CAR T cells to recognize and attack cells expressing PITAR, these therapies could enhance the immune response against glioblastoma and improve treatment outcomes for patients. Overall, the cancer/testis expression profile of PITAR provides a promising foundation for the development of targeted immunotherapies for glioblastoma.