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.
Cancer cell. 2025 Apr 17 [Epub]
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 Macarios, 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
Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China., Department of Chemistry, University of Toronto, Toronto, ON, Canada., Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada., Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China., Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA., Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada., Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada., Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. Electronic address: ., Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. Electronic address: ., Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address: .