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

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

doi:10.1016/j.ccell.2025.03.027

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

Cancer Cell. 2025 May 12;43(5):891-904.e10. doi: 10.1016/j.ccell.2025.03.027. Epub 2025 Apr 17.

Authors

Mona Teng¹, Jiacheng Guo², Xin Xu³, Xinpei Ci³, Yulin Mo⁴, Yakup Kohen¹, Zuyao Ni³, Sujun Chen³, Wang Yuan Guo³, Martin Bakht⁵, Shengyu Ku⁵, Michael Sigouros⁶, Wenqin Luo⁷, Colette Maya Macarios⁸, Ziting Xia⁹, Moliang Chen³, Sami Ul Haq³, Wen Yang¹⁰, Alejandro Berlin³, Theo van der Kwast³, Leigh Ellis¹¹, Amina Zoubeidi¹², Gang Zheng⁴, Jie Ming¹⁰, Yuzhuo Wang¹², Haissi Cui⁸, Benjamin H Lok¹³, Brian Raught¹, Himisha Beltran¹⁴, Jun Qin¹⁵, Housheng Hansen He¹⁶

Affiliations

¹ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
⁶ Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷ Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ Department of Chemistry, University of Toronto, Toronto, ON, Canada.
⁹ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹¹ 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.
¹² Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹³ 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.
¹⁴ Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA. Electronic address: himisha_beltran@dfci.harvard.edu.
¹⁵ Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China. Electronic address: qinjun@sibs.ac.cn.
¹⁶ 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: hansen.he@uhn.ca.

PMID: 40250444
DOI: 10.1016/j.ccell.2025.03.027

Abstract

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.

Keywords: RNA protein interactions; circular RNA; lineage plasticity; neuroedocrine prostate cancer; noncoding RNA; small cell lung cancer; transcription factors.

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Line, Tumor
Cell Lineage
Cell Transdifferentiation* / genetics
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
Mice
Mice, Knockout
Neuroendocrine Tumors* / genetics
Neuroendocrine Tumors* / pathology
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
RNA, Circular* / genetics
RNA, Circular* / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Thyroid Nuclear Factor 1* / genetics
Thyroid Nuclear Factor 1* / metabolism
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
SOXB1 Transcription Factors
RNA, Circular
Thyroid Nuclear Factor 1
ASCL1 protein, human
SOX2 protein, human
Transcription Factors
NKX2-1 protein, human
Nkx2-1 protein, mouse