Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Circular RNAs (circRNAs) are noncoding RNAs with regulatory functions.
• The role of circRNAs in the transdifferentiation of adenocarcinoma into neuroendocrine cancers is largely unknown.

Purpose of the Study:

• To investigate the role of circRNAs in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC).
• To identify specific circRNAs involved in this process and elucidate their mechanisms of action.

Main Methods:

• Identification and quantification of circRNAs in NEPC and SCLC patient samples.
• Functional studies using RNA interference (shRNA, siRNA) and gene editing (CRISPR-Cas13, Cas9) to assess the impact of circRMST.
• Analysis of protein degradation pathways (autophagy-lysosomal) and transcription factor binding (NKX2-1, SOX2).
• Genetic knockout models in mice to study the in vivo effects of Rmst.

Main Results:

• circRMST was identified as a highly abundant circRNA in NEPC and SCLC, conserved across species.
• circRMST is essential for tumor growth and the expression of ASCL1, a key regulator of neuroendocrine differentiation.
• Genetic knockout of Rmst in mouse models inhibited neuroendocrine transdifferentiation, preserving the adenocarcinoma phenotype.
• circRMST physically interacts with transcription factors NKX2-1 and SOX2.
• Loss of circRMST led to NKX2-1 protein degradation via autophagy and altered SOX2 genomic binding, resulting in decreased ASCL1 transcription.

Conclusions:

• circRMST plays a critical role in the transdifferentiation of adenocarcinoma into NEPC and SCLC.
• circRMST is a potential therapeutic target for neuroendocrine cancers.
• The mechanism involves circRMST’s interaction with NKX2-1 and SOX2, regulating ASCL1 expression and cellular fate.