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miR-101–3p may play a therapeutic role in various tumours. However, its anti-tumour mechanism remains unclear, and a definitive strategy to treat tumour cells in vivo is lacking. The objective of this study was to investigate the inhibitory mechanism of miR-101–3p on tumour cells and to develop relevant nanomedicines for in vivo therapy. The expression levels of miR-101–3p and its target protein TBLR1 in tumour tissues and cells were detected, and their relationship with ferroptosis was clarified. Furthermore, the efficacy of nanocarriers in achieving in vivo therapeutic gene delivery was evaluated. Nanomedicine was further developed, with the anti-proliferative in vivo therapeutic effect validated using a subcutaneous xenograft cancer model. The expression level of miR-101–3p negatively correlated with clinical tumour size and TNM stage. miR-101–3p restores ferroptosis in tumour cells by directly targeting TBLR1, which in turn promotes apoptosis and inhibits proliferation. We developed nanomedicine that can deliver miR-101–3p to tumour cells in vivo to achieve ferroptosis recovery, as well as to inhibit in vivo tumour proliferation. The miR-101–3p/TBLR1 axis plays an important role in tumour ferroptosis. Nanopharmaceuticals that increase miR-101–3p levels may be effective therapies to inhibit tumour proliferation.

// Soo-Yeon Park 1, * , Younghwa Na 2, * , Mee-Hee Lee 1, * , Jae-Sung Seo 1 , Yoo-Hyun Lee 3 , Kyung-Chul Choi 4 , Hyo-Kyoung Choi 5 , Ho-Geun Yoon 1 1 Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea 2 College of Pharmacy, CHA University, Gyeonggi-do, Pocheon, South Korea 3 Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea 4 Department of Biomedical Sciences, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, South Korea 5 Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea * These authors contributed equally to this work Correspondence to: Kyung-Chul Choi, email: choikc75@amc.seoul.kr Hyo-Kyoung Choi, email: chkyoung@kfri.re.kr Ho-Geun Yoon, email: yhgeun@yuhs.ac Keywords: SUMOylation, TBL1, TBLR1, NF-κB, inflammation Received: October 29, 2015 Accepted: March 29, 2016 Published: April 26, 2016 ABSTRACT Chronic inflammation is strongly associated with prostate cancer pathogenesis. Transducin β-like protein (TBL1) and Transducin β-like 1X-linked receptor 1 (TBLR1) have been identified recently as a coactivator for NF-κB-mediated transcription; however, the underlying mechanism by which TBL1 and TBLR1 activate NF-κB function during inflammation remains unknown. Here, we demonstrate that cytokine production is significantly elevated in androgen-independent PC-3 prostate cancer cells compared with androgen-dependent LNCaP prostate cancer cells. Elevated cytokine production positively correlates with the TBL1 and TBLR1 SUMOylation level in PC-3 cells. We show that both TBL1 and TBLR1 are SUMOylated in response to TNF-α treatment, and this increases formation of the TBL1-TBLR1-NF-κB complex, which leads to NF-κB-mediated transcriptional activation of cytokine gene expression. Conversely, SENP1-mediated deSUMOylation of TBL1 and TBLR1 inhibits NF-κB-target gene expression by dissociating TBL1 and TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex. TBL1 knockdown substantially suppresses inflammatory signaling and PC-3 cell proliferation. Collectively, these results suggest that targeted SUMOylation of TBL1 and TBLR1 may be a useful strategy for therapeutic treatment of androgen-independent prostate cancer.