Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer

Yongyong Yang; Ting You Wang; Qianru Li; Jiawen Lu; Yanan Ren; Adam B. Weiner; Joshua Fry; Qi Liu; Chaehyun Yum; Rui Wang; Qingxiang Guo; Yu Wan; Zhe Ji; Xuesen Dong; Tamara L. Lotan; Edward Matthew Schaeffer; Rendong Yang; Qi Cao

doi:10.1126/sciadv.adk6989

Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer

Yongyong Yang, Ting You Wang, Qianru Li, Jiawen Lu, Yanan Ren, Adam B. Weiner, Joshua Fry, Qi Liu, Chaehyun Yum, Rui Wang, Qingxiang Guo, Yu Wan, Zhe Ji, Xuesen Dong, Tamara L. Lotan, Edward Matthew Schaeffer, Rendong Yang^*, Qi Cao^*

^*Corresponding author for this work

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

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Abstract

Mounting evidence indicates that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we found an lncRNA, PCa-associated transcript 71 (PRCAT71), highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells and androgen receptor (AR) signaling. Mechanistically, PRCAT71 acts as a scaffold to recruit K homology (KH)–type splicing regulatory protein (KHSRP) to AR messenger RNA (mRNA) and stabilize AR mRNA, leading to activated AR signaling. KHSRP plays a critical role in PCa progression. PRCAT71 is transcriptionally regulated by AR-driven enhancers, forming a positive regulatory loop between AR and PRCAT71 in PCa. Our study demonstrates a coordinated regulation of AR mRNA by lncRNA PRCAT71 and RNA binding protein KHSRP and provides insight that the PRCAT71-KHSRP-AR axis is a promising therapeutic target for treating PCa.

Original language	English (US)
Article number	eadk6989
Journal	Science Advances
Volume	11
Issue number	15
DOIs	https://doi.org/10.1126/sciadv.adk6989
State	Published - Apr 11 2025

Funding

Imaging work was performed at the Northwestern University Center for Advanced Microscopy (RRID: SCR_020996) generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This work is supported in part by grants from the Department of Defense W81XWH-21-1-0146 (Y.Y.), HT9425-23-1-0491 (Y.Y.), and W81XWH-20-1-0504 (Q.C.); NIH R01CA278832 (Q.C.), R01CA256741 (Q.C.), R01CA285684 (Q.C.), R01CA259388 (R.Y.), R35GM142441 (R.Y.), R35GM138192 (Z.J.), and R01HL161389 (Z.J.); Canadian Institute of Health Research PJT156150 (X.D.), PJT178063 (X.D.), and PJT196012 (X.D.); Prostate SPORE P50CA180995 Development Research Program (Q.C. and R.Y.); and the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital (Q.C. and R.Y.).

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Yang, Y., Wang, T. Y., Li, Q., Lu, J., Ren, Y., Weiner, A. B., Fry, J., Liu, Q., Yum, C., Wang, R., Guo, Q., Wan, Y., Ji, Z., Dong, X., Lotan, T. L., Schaeffer, E. M., Yang, R., & Cao, Q. (2025). Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer. Science Advances, 11(15), Article eadk6989. https://doi.org/10.1126/sciadv.adk6989

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title = "Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer",

abstract = "Mounting evidence indicates that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we found an lncRNA, PCa-associated transcript 71 (PRCAT71), highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells and androgen receptor (AR) signaling. Mechanistically, PRCAT71 acts as a scaffold to recruit K homology (KH)–type splicing regulatory protein (KHSRP) to AR messenger RNA (mRNA) and stabilize AR mRNA, leading to activated AR signaling. KHSRP plays a critical role in PCa progression. PRCAT71 is transcriptionally regulated by AR-driven enhancers, forming a positive regulatory loop between AR and PRCAT71 in PCa. Our study demonstrates a coordinated regulation of AR mRNA by lncRNA PRCAT71 and RNA binding protein KHSRP and provides insight that the PRCAT71-KHSRP-AR axis is a promising therapeutic target for treating PCa.",

author = "Yongyong Yang and Wang, {Ting You} and Qianru Li and Jiawen Lu and Yanan Ren and Weiner, {Adam B.} and Joshua Fry and Qi Liu and Chaehyun Yum and Rui Wang and Qingxiang Guo and Yu Wan and Zhe Ji and Xuesen Dong and Lotan, {Tamara L.} and Schaeffer, {Edward Matthew} and Rendong Yang and Qi Cao",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = apr,

day = "11",

doi = "10.1126/sciadv.adk6989",

language = "English (US)",

volume = "11",

journal = "Science Advances",

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Yang, Y, Wang, TY, Li, Q, Lu, J, Ren, Y, Weiner, AB, Fry, J, Liu, Q, Yum, C, Wang, R, Guo, Q, Wan, Y, Ji, Z, Dong, X, Lotan, TL, Schaeffer, EM , Yang, R & Cao, Q 2025, 'Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer', Science Advances, vol. 11, no. 15, eadk6989. https://doi.org/10.1126/sciadv.adk6989

TY - JOUR

T1 - Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer

AU - Yang, Yongyong

AU - Wang, Ting You

AU - Li, Qianru

AU - Lu, Jiawen

AU - Ren, Yanan

AU - Weiner, Adam B.

AU - Fry, Joshua

AU - Liu, Qi

AU - Yum, Chaehyun

AU - Wang, Rui

AU - Guo, Qingxiang

AU - Wan, Yu

AU - Ji, Zhe

AU - Dong, Xuesen

AU - Lotan, Tamara L.

AU - Schaeffer, Edward Matthew

AU - Yang, Rendong

AU - Cao, Qi

PY - 2025/4/11

Y1 - 2025/4/11

N2 - Mounting evidence indicates that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we found an lncRNA, PCa-associated transcript 71 (PRCAT71), highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells and androgen receptor (AR) signaling. Mechanistically, PRCAT71 acts as a scaffold to recruit K homology (KH)–type splicing regulatory protein (KHSRP) to AR messenger RNA (mRNA) and stabilize AR mRNA, leading to activated AR signaling. KHSRP plays a critical role in PCa progression. PRCAT71 is transcriptionally regulated by AR-driven enhancers, forming a positive regulatory loop between AR and PRCAT71 in PCa. Our study demonstrates a coordinated regulation of AR mRNA by lncRNA PRCAT71 and RNA binding protein KHSRP and provides insight that the PRCAT71-KHSRP-AR axis is a promising therapeutic target for treating PCa.

AB - Mounting evidence indicates that long noncoding RNAs (lncRNAs) play vital roles in tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in prostate cancer (PCa) are still largely unknown. In this study, we found an lncRNA, PCa-associated transcript 71 (PRCAT71), highly expressed in metastatic and primary PCa compared to benign prostate tissues. Silencing PRCAT71 inhibited cancerous properties of PCa cells and androgen receptor (AR) signaling. Mechanistically, PRCAT71 acts as a scaffold to recruit K homology (KH)–type splicing regulatory protein (KHSRP) to AR messenger RNA (mRNA) and stabilize AR mRNA, leading to activated AR signaling. KHSRP plays a critical role in PCa progression. PRCAT71 is transcriptionally regulated by AR-driven enhancers, forming a positive regulatory loop between AR and PRCAT71 in PCa. Our study demonstrates a coordinated regulation of AR mRNA by lncRNA PRCAT71 and RNA binding protein KHSRP and provides insight that the PRCAT71-KHSRP-AR axis is a promising therapeutic target for treating PCa.

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Androgen receptor–regulated lncRNA PRCAT71 promotes AR signaling through the interaction with KHSRP in prostate cancer

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