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

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 KwastLeigh Ellis, Amina Zoubeidi, Gang Zheng, Jie Ming, Yuzhuo Wang, Haissi Cui, Benjamin H. Lok, Brian Raught, Himisha Beltran^*, Jun Qin^*, Housheng Hansen He^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English
Pages (from-to)	891-904.e10
Journal	Cancer Cell
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2025.03.027
State	Published - 12 May 2025

Keywords

circular RNA
lineage plasticity
neuroedocrine prostate cancer
noncoding RNA
RNA protein interactions
small cell lung cancer
transcription factors

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10.1016/j.ccell.2025.03.027

Cite this

Teng, M., Guo, J., Xu, X., Ci, X., Mo, Y., Kohen, Y., Ni, Z., Chen, S., Guo, W. Y., Bakht, M., Ku, S., Sigouros, M., Luo, W., Macarios, C. M., Xia, Z., Chen, M., Ul Haq, S., Yang, W., Berlin, A., ... He, H. H. (2025). Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation. Cancer Cell, 43(5), 891-904.e10. https://doi.org/10.1016/j.ccell.2025.03.027

@article{fcacb85da9434026b1a0636db9f73f9d,

title = "Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation",

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 = "circular RNA, lineage plasticity, neuroedocrine prostate cancer, noncoding RNA, RNA protein interactions, small cell lung cancer, transcription factors",

author = "Mona Teng and Jiacheng Guo and Xin Xu and Xinpei Ci and Yulin Mo and Yakup Kohen and Zuyao Ni and Sujun Chen and Guo, {Wang Yuan} and Martin Bakht and Shengyu Ku and Michael Sigouros and Wenqin Luo and Macarios, {Colette Maya} and Ziting Xia and Moliang Chen and {Ul Haq}, Sami and Wen Yang and Alejandro Berlin and {van der Kwast}, Theo and Leigh Ellis and Amina Zoubeidi and Gang Zheng and Jie Ming and Yuzhuo Wang and Haissi Cui and Lok, {Benjamin H.} and Brian Raught and Himisha Beltran and Jun Qin and He, {Housheng Hansen}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = may,

day = "12",

doi = "10.1016/j.ccell.2025.03.027",

language = "English",

volume = "43",

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Teng, M, Guo, J, Xu, X, Ci, X, Mo, Y, Kohen, Y, Ni, Z, Chen, S, Guo, WY, Bakht, M, Ku, S, Sigouros, M, Luo, W, Macarios, CM, Xia, Z, Chen, M, Ul Haq, S, Yang, W, Berlin, A, van der Kwast, T, Ellis, L, Zoubeidi, A, Zheng, G, Ming, J, Wang, Y, Cui, H, Lok, BH, Raught, B, Beltran, H, Qin, J & He, HH 2025, 'Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation', Cancer Cell, vol. 43, no. 5, pp. 891-904.e10. https://doi.org/10.1016/j.ccell.2025.03.027

TY - JOUR

T1 - Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation

AU - Teng, Mona

AU - Guo, Jiacheng

AU - Xu, Xin

AU - Ci, Xinpei

AU - Mo, Yulin

AU - Kohen, Yakup

AU - Ni, Zuyao

AU - Chen, Sujun

AU - Guo, Wang Yuan

AU - Bakht, Martin

AU - Ku, Shengyu

AU - Sigouros, Michael

AU - Luo, Wenqin

AU - Macarios, Colette Maya

AU - Xia, Ziting

AU - Chen, Moliang

AU - Ul Haq, Sami

AU - Yang, Wen

AU - Berlin, Alejandro

AU - van der Kwast, Theo

AU - Ellis, Leigh

AU - Zoubeidi, Amina

AU - Zheng, Gang

AU - Ming, Jie

AU - Wang, Yuzhuo

AU - Cui, Haissi

AU - Lok, Benjamin H.

AU - Raught, Brian

AU - Beltran, Himisha

AU - Qin, Jun

AU - He, Housheng Hansen

PY - 2025/5/12

Y1 - 2025/5/12

N2 - 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.

AB - 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.

KW - circular RNA

KW - lineage plasticity

KW - neuroedocrine prostate cancer

KW - noncoding RNA

KW - RNA protein interactions

KW - small cell lung cancer

KW - transcription factors

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DO - 10.1016/j.ccell.2025.03.027

M3 - Article

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