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

Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. It is unexplored how they may be functionally involved in the transdifferentiation of prostate and lung adenocarcinoma to neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC). Here we identified an exceptionally abundant circRNA circRMST predominantly expressed in NEPC and SCLC and conserved between humans and mice. Using shRNA, siRNA, CRISPR-Cas13 and Cas9, we consistently showed that circRMST is essential for tumour growth and for the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models led to a prevention of neuroendocrine transdifferentiation and sustained tumours in adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, which collectively leads to the loss of ASCL1 transcription.