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

• DOI: 10.1016/j.ccell.2025.03.027
• Publication Date: 2025-04-17T14:34:21Z
• Authors: Mona Teng; Jiacheng Guo; Xin Xu; Xinpei Ci; Yulin Mo; Yakup Kohen; Zuyao Ni; Sujun Chen; Wang Yuan Guo; Martin Bakht; Shengyu Ku; Michael Sigouros; Wenqin Luo; Colette Maya Maca...; Ziting Xia; Moliang Chen; Sami Ul Haq; Wen Yang; Alejandro Berlin; Theo van der Kwast; Leigh Ellis; Amina Zoubeidi; Gang Zheng; Jie Ming; Yuzhuo Wang; Haissi Cui; Benjamin H. Lok; Brian Raught; Himisha Beltran; Jun Qin; Housheng Hansen He
• Keywords: Transdifferentiation; Lineage (genetic)

Circular RNA (circRNA) is a class of noncoding with regulatory potentials. Its role in the transdifferentiation prostate and lung adenocarcinoma into neuroendocrine cancer (NEPC) small cell (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed NEPC SCLC, strong conservation between humans mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, Cas9 consistently demonstrate that essential for tumor growth expression ASCL1, master regulator fate. Genetic knockout Rmst genetic engineered mouse models prevents transdifferentiation, maintaining tumors state. Mechanistically, physically interacts lineage transcription factors NKX2-1 SOX2. Loss induces protein degradation through autophagy-lysosomal pathway alters genomic binding SOX2, collectively leading to loss ASCL1 transcription.