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Theranostics 2020; 10(25):11775-11793. doi:10.7150/thno.51655 This issue Cite

Research Paper

SLC14A1 prevents oncometabolite accumulation and recruits HDAC1 to transrepress oncometabolite genes in urothelial carcinoma

Ti-Chun Chan^1,2,3, Wen-Jeng Wu^4,5,6,7,8,9, Wei-Ming Li^5,6,7,9,10, Meng-Shin Shiao¹¹, Yow-Ling Shiue^2,12,✉, Chien-Feng Li^{1,3,12,13,✉}

1. Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
2. Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
3. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
4. Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
5. Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
6. Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
7. Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan, Kaohsiung, Taiwan
8. Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
9. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
10. Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan
11. Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
12. Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
13. Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

✉ Corresponding authors: Chien-Feng Li, MD, PhD, Department of Medical Research, Chi Mei Medical Center, 901 Chunghwa Road, Yung Kang Dist., Tainan City 710, Taiwan. Phone: +886-6-2812811 ext. 53680; E-mail: angelo.pcom.tw. Yow-Ling Shiue, PhD, Institute of Biomedical Sciences, National Sun Yat-Sen University, 70 Lienhai Road, Gushan Dist., Kaohsiung City 804, Taiwan. Phone: +886-7-525-2000 ext. 5818; E-mail: shirleynsysu.edu.tw More

Abstract

Urothelial carcinoma (UC), including upper tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC), is a common malignant disease in developed countries. Oncogenic metabolic lesions have been associated with UC development.

Methods: Using data mining, a series of studies were performed to study the involvement of SLC14A1 in UC specimens, animal models and UC-derived cell lines.

Results: In two cohorts of UTUC (n = 340) and UBUC (n = 295), the SLC14A1 protein level was an independent prognostic factor. Epigenetic silencing contributed to SLC14A1 downregulation in UCs. Total and membranous SLC14A1 played tumor suppressive roles through the inhibition of cell proliferation and metastasis in distinct UC-derived cells and animal models. Functional SLC14A1 prevented the accumulation of arginine and urea, enhanced mitochondrial fusion and aerobic respiration, inhibited glycolysis by altering the expression levels of several related proteins and sensitized arginine-deprivation treatment in ASS1-deficient UC-derived cells. In vitro and in vivo, SLC14A1 inhibited the mTOR signaling pathway and subsequently tumorigenesis, supported by reduced arginine concentrations in vitro. Nuclear SLC14A1 transrepressed HK2 and DEGS1 genes via recruitment of HDAC1 and/or SIN3A to maintain metabolic homeostasis and thereafter impeded tumorigenesis.

Conclusion: Clinical associations, animal models and in vitro indications provide solid evidence that the SLC14A1 gene is a novel tumor suppressor in UCs. Total and membranous SLC14A1 prevents urea and arginine accumulation via the mTOR signaling pathway. Nuclear SLC14A1 recruits HDAC1 to transrepress oncometabolite genes.

Keywords: SLC14A1, arginine, urea, HK2, DEGS1, MTOR

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