Cancer cell · 2025
Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation.
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Teng Mona, Guo Jiacheng, Xu Xin, Ci Xinpei, Mo Yulin, Kohen Yakup, Ni Zuyao, Chen Sujun, Guo Wang Yuan, Bakht Martin, Ku Shengyu, Sigouros Michael, Luo Wenqin, Macarios Colette Maya, Xia Ziting, Chen Moliang, Ul Haq Sami, Yang Wen, Berlin Alejandro, van der Kwast Theo, Ellis Leigh, Zoubeidi Amina, Zheng Gang, Ming Jie, Wang Yuzhuo, Cui Haissi, Lok Benjamin H, Raught Brian, Beltran Himisha, Qin Jun, He Housheng Hansen
Аннотация
Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an 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, collectively leading to the loss of ASCL1 transcription.