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Mol. Cells

Published online January 3, 2022

© The Korean Society for Molecular and Cellular Biology

Menin Enhances Androgen Receptor-Independent Proliferation and Migration of Prostate Cancer Cells

Taewan Kim1,4 , Kwanyoung Jeong1,4 , Eunji Kim1 , Kwanghyun Yoon1 , Jinmi Choi1 , Jae Hyeon Park1 , Jae-Hwan Kim2,3 , Hyung Sik Kim1 , Hong-Duk Youn3 , and Eun-Jung Cho1,*

1School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea, 2NineBiopharm, Co., Ltd., Cheongju 28161, Korea, 3National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea, 4These authors contributed equally to this work.

Correspondence to : echo@skku.edu

Received: August 3, 2021; Revised: November 19, 2021; Accepted: December 7, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

The androgen receptor (AR) is an important therapeutic target for treating prostate cancer (PCa). Moreover, there is an increasing need for understanding the AR-independent progression of tumor cells such as neuroendocrine prostate cancer (NEPC). Menin, which is encoded by multiple endocrine neoplasia type 1 (MEN1), serves as a direct link between AR and the mixed-lineage leukemia (MLL) complex in PCa development by activating AR target genes through histone H3 lysine 4 methylation. Although menin is a critical component of AR signaling, its tumorigenic role in AR-independent PCa cells remains unknown. Here, we compared the role of menin in AR-positive and AR-negative PCa cells via RNAi-mediated or pharmacological inhibition of menin. We demonstrated that menin was involved in tumor cell growth and metastasis in PCa cells with low or deficient levels of AR. The inhibition of menin significantly diminished the growth of PCa cells and induced apoptosis, regardless of the presence of AR. Additionally, transcriptome analysis showed that the expression of many metastasis-associated genes was perturbed by menin inhibition in AR-negative DU145 cells. Furthermore, wound-healing assay results showed that menin promoted cell migration in AR-independent cellular contexts. Overall, these findings suggest a critical function of menin in tumorigenesis and provide a rationale for drug development against menin toward targeting high-risk metastatic PCa, especially those independent of AR.

Keywords androgen receptor, menin, menin inhibitor, metastasis, prostate cancer

Article

On-line First

Mol. Cells

Published online January 3, 2022

Copyright © The Korean Society for Molecular and Cellular Biology.

Menin Enhances Androgen Receptor-Independent Proliferation and Migration of Prostate Cancer Cells

Taewan Kim1,4 , Kwanyoung Jeong1,4 , Eunji Kim1 , Kwanghyun Yoon1 , Jinmi Choi1 , Jae Hyeon Park1 , Jae-Hwan Kim2,3 , Hyung Sik Kim1 , Hong-Duk Youn3 , and Eun-Jung Cho1,*

1School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea, 2NineBiopharm, Co., Ltd., Cheongju 28161, Korea, 3National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea, 4These authors contributed equally to this work.

Correspondence to:echo@skku.edu

Received: August 3, 2021; Revised: November 19, 2021; Accepted: December 7, 2021

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

The androgen receptor (AR) is an important therapeutic target for treating prostate cancer (PCa). Moreover, there is an increasing need for understanding the AR-independent progression of tumor cells such as neuroendocrine prostate cancer (NEPC). Menin, which is encoded by multiple endocrine neoplasia type 1 (MEN1), serves as a direct link between AR and the mixed-lineage leukemia (MLL) complex in PCa development by activating AR target genes through histone H3 lysine 4 methylation. Although menin is a critical component of AR signaling, its tumorigenic role in AR-independent PCa cells remains unknown. Here, we compared the role of menin in AR-positive and AR-negative PCa cells via RNAi-mediated or pharmacological inhibition of menin. We demonstrated that menin was involved in tumor cell growth and metastasis in PCa cells with low or deficient levels of AR. The inhibition of menin significantly diminished the growth of PCa cells and induced apoptosis, regardless of the presence of AR. Additionally, transcriptome analysis showed that the expression of many metastasis-associated genes was perturbed by menin inhibition in AR-negative DU145 cells. Furthermore, wound-healing assay results showed that menin promoted cell migration in AR-independent cellular contexts. Overall, these findings suggest a critical function of menin in tumorigenesis and provide a rationale for drug development against menin toward targeting high-risk metastatic PCa, especially those independent of AR.

Keywords: androgen receptor, menin, menin inhibitor, metastasis, prostate cancer

Mol. Cells
Dec 31, 2021 Vol.44 No.12, pp. 861~919
COVER PICTURE
Structure of the fly peripheral neurons in the fly head. Flies have basic sensory organs including eyes for vision, antennae and maxillary palps for olfaction, and proboscis (magenta) for gustation which can be labelled with monoclonal antibody 22C10. The figure is a 3D reconstructed image with 30 slices of confocal sections with 3 μm interval. It shows that the proboscis is required for sensing attractive carboxylic acids such as glycolic acid, citric acid, and lactic acid (Shrestha and Lee, pp. 900-910).

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