Decoding the lncRNAome Across Diverse Cellular Stresses Reveals Core p53-effector Pan-cancer Suppressive lncRNAs

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Long non-coding RNAs (lncRNAs) play roles in cancer, but their regulation and function are often unknown.
• The tumor suppressor p53 is a critical regulator in cancer, but its direct transcriptional targets, including lncRNAs, are not fully characterized.

Purpose of the Study:

• To identify and characterize core p53-regulated lncRNAs across multiple cancer types.
• To investigate the functional roles of these lncRNAs in tumor suppression and their association with patient survival.

Main Methods:

• Integrated computational and experimental approaches, including pan-cancer RNAi/CRISPR screens, genomic, epigenetic, and expression profiles (single-cell RNA sequencing).
• Analysis of p53-dependent transcriptional regulation under various cellular stresses.
• Experimental validation using independent datasets, patient cohorts, and cell-based assays.

Main Results:

• Identified a set of core lncRNAs directly transactivated by p53 across diverse cancer types and cellular stresses.
• These lncRNAs consistently suppressed cancer cell survival and growth and were associated with improved patient survival.
• A specific lncRNA, PTSL, was found to inhibit proliferation and induce G2 cell-cycle arrest by modulating the G2 regulatory network.

Conclusions:

• Elucidated previously unknown, high-confidence p53-targeted lncRNAs that function as tumor suppressors.
• Revealed the role of these lncRNAs in the p53-mediated cell-cycle regulation and their impact on cancer progression and patient outcomes.