Down-regulation of SLC14A1 in prostate cancer activates CDK1/CCNB1 and mTOR pathways and promotes tumor progression.
Humans
Male
Prostatic Neoplasms
/ genetics
TOR Serine-Threonine Kinases
/ metabolism
Gene Expression Regulation, Neoplastic
Disease Progression
Signal Transduction
Cell Line, Tumor
CDC2 Protein Kinase
/ metabolism
DNA Methylation
Promoter Regions, Genetic
Cell Proliferation
/ genetics
Down-Regulation
Prognosis
Cell Movement
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 Jun 2024
28 Jun 2024
Historique:
received:
03
02
2024
accepted:
26
06
2024
medline:
29
6
2024
pubmed:
29
6
2024
entrez:
28
6
2024
Statut:
epublish
Résumé
Prostate cancer (PCa) is the most common cancer among men in the United States and the leading cause of cancer-related death. The Solute Carrier Family 14 Member 1 (SLC14A1) is a member of urea transporters which are important for the regulation of urine concentration. However, the physiological significance of SLC14A1 in PCa still remains unclear. In the present study, via bioinformatics analysis and experiments, we found that expression of SLC14A1 is significantly decreased in PCa progression, which could be attributed to hypermethylation on SLC14A1 promoter region. Moreover, its low expression and hypermethylation on SLC14A1 promoter are closely related to the poor prognosis of PCa patients. On the other hand, overexpression of SLC14A1 inhibited cell proliferation and metastasis while its overexpression also suppressed CDK1/CCNB1 pathway and mTOR/MMP-9 signaling pathway. Additionally, SLC14A1 expression is enriched in prostate basal-type cells. In summary, our study indicates that its low expression level and promoter hypermethylation of SLC14A1 may represent novel indicators for PCa progression and prognosis, and SLC14A1 could inhibit the progression of PCa.
Identifiants
pubmed: 38942821
doi: 10.1038/s41598-024-66020-1
pii: 10.1038/s41598-024-66020-1
doi:
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
MTOR protein, human
EC 2.7.1.1
CDC2 Protein Kinase
EC 2.7.11.22
CDK1 protein, human
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14914Subventions
Organisme : National Natural Science Foundation of China
ID : 82303836
Organisme : National Natural Science Foundation of China
ID : 82172797
Informations de copyright
© 2024. The Author(s).
Références
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30. https://doi.org/10.3322/caac.21442 (2018).
doi: 10.3322/caac.21442
pubmed: 29313949
Leibold, J. et al. Somatic tissue engineering in mouse models reveals an actionable role for WNT pathway alterations in prostate cancer metastasis. Cancer Discov. 10, 1038–1057. https://doi.org/10.1158/2159-8290.CD-19-1242 (2020).
doi: 10.1158/2159-8290.CD-19-1242
pubmed: 32376773
pmcid: 7334089
Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl. Acad. Sci. U.S.A 116, 11428–11436. https://doi.org/10.1073/pnas.1902651116 (2019).
doi: 10.1073/pnas.1902651116
pubmed: 31061129
pmcid: 6561293
Wang, G., Zhao, D., Spring, D. J. & DePinho, R. A. Genetics and biology of prostate cancer. Genes Dev. 32, 1105–1140. https://doi.org/10.1101/gad.315739.118 (2018).
doi: 10.1101/gad.315739.118
pubmed: 30181359
pmcid: 6120714
Nyquist, M. D. et al. Combined TP53 and RB1 loss promotes prostate cancer resistance to a spectrum of therapeutics and confers vulnerability to replication stress. Cell Rep. 31, 107669. https://doi.org/10.1016/j.celrep.2020.107669 (2020).
doi: 10.1016/j.celrep.2020.107669
pubmed: 32460015
pmcid: 7453577
Attard, G. et al. Prostate cancer. Lancet 387, 70–82. https://doi.org/10.1016/s0140-6736(14)61947-4 (2016).
doi: 10.1016/s0140-6736(14)61947-4
pubmed: 26074382
Phé, V., Cussenot, O. & Rouprêt, M. Methylated genes as potential biomarkers in prostate cancer. BJU Int. 105, 1364–1370. https://doi.org/10.1111/j.1464-410X.2009.09167.x (2010).
doi: 10.1111/j.1464-410X.2009.09167.x
pubmed: 20067451
Guo, H. et al. DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs. Cell 186, 2765-2782.e2728. https://doi.org/10.1016/j.cell.2023.05.028 (2023).
doi: 10.1016/j.cell.2023.05.028
pubmed: 37327786
pmcid: 10436379
Chao, C. R. et al. Genome-wide methylation profiling of diagnostic tumor specimens identified DNA methylation markers associated with metastasis among men with untreated localized prostate cancer. Cancer Med. 12, 18837–18849. https://doi.org/10.1002/cam4.6507 (2023).
doi: 10.1002/cam4.6507
pubmed: 37694549
pmcid: 10557825
Wang, Z. A. et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat. Cell Biol. 15, 274–283. https://doi.org/10.1038/ncb2697 (2013).
doi: 10.1038/ncb2697
pubmed: 23434823
pmcid: 3743266
Zhang, D., Zhao, S., Li, X., Kirk, J. S. & Tang, D. G. Prostate luminal progenitor cells in development and cancer. Trends Cancer 4, 769–783. https://doi.org/10.1016/j.trecan.2018.09.003 (2018).
doi: 10.1016/j.trecan.2018.09.003
pubmed: 30352679
pmcid: 6212301
Yahouedehou, S. et al. Sickle cell anemia: Variants in the CYP2D6, CAT, and SLC14A1 genes are associated with improved hydroxyurea response. Front. Pharmacol. 11, 553064. https://doi.org/10.3389/fphar.2020.553064 (2020).
doi: 10.3389/fphar.2020.553064
pubmed: 33013391
pmcid: 7510454
Chan, T. C. et al. SLC14A1 prevents oncometabolite accumulation and recruits HDAC1 to transrepress oncometabolite genes in urothelial carcinoma. Theranostics 10, 11775–11793. https://doi.org/10.7150/thno.51655 (2020).
doi: 10.7150/thno.51655
pubmed: 33052246
pmcid: 7546005
Hou, R. et al. Identification of a novel UT-B urea transporter in human urothelial cancer. Front. Physiol. 8, 245. https://doi.org/10.3389/fphys.2017.00245 (2017).
doi: 10.3389/fphys.2017.00245
pubmed: 28503151
pmcid: 5409228
de Maturana, E. L. et al. Bladder cancer genetic susceptibility. A systematic review. Bladder Cancer 4, 215–226. https://doi.org/10.3233/BLC-170159 (2018).
doi: 10.3233/BLC-170159
pubmed: 29732392
pmcid: 5929300
Ma, Z. et al. Interferon-dependent SLC14A1(+) cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell 40, 1550–1565. https://doi.org/10.1016/j.ccell.2022.11.005 (2022).
doi: 10.1016/j.ccell.2022.11.005
pubmed: 36459995
Ye, B., Ding, K., Li, K. & Zhu, Q. Study on the role of SLC14A1 gene in biochemical recurrence of prostate cancer. Sci. Rep. 12, 17064. https://doi.org/10.1038/s41598-022-20775-7 (2022).
doi: 10.1038/s41598-022-20775-7
pubmed: 36257969
pmcid: 9579171
Vaarala, M. H., Hirvikoski, P., Kauppila, S. & Paavonen, T. K. Identification of androgen-regulated genes in human prostate. Mol. Med. Rep. 6, 466–472. https://doi.org/10.3892/mmr.2012.956 (2012).
doi: 10.3892/mmr.2012.956
pubmed: 22735730
pmcid: 3493087
Del Castillo Falconi, V. M., Torres-Arciga, K., Matus-Ortega, G., Diaz-Chavez, J. & Herrera, L. A. DNA Methyltransferases: From evolution to clinical applications. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23168994 (2022).
doi: 10.3390/ijms23168994
pubmed: 36361550
pmcid: 9654283
Fang, L. et al. GRNdb: Decoding the gene regulatory networks in diverse human and mouse conditions. Nucleic Acids Res. 49, D97–D103. https://doi.org/10.1093/nar/gkaa995 (2021).
doi: 10.1093/nar/gkaa995
pubmed: 33151298
Pinero, J. et al. DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 45, D833–D839. https://doi.org/10.1093/nar/gkw943 (2017).
doi: 10.1093/nar/gkw943
pubmed: 27924018
Jia, J. et al. KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy. Theranostics 9, 5464–5477. https://doi.org/10.7150/thno.33282 (2019).
doi: 10.7150/thno.33282
pubmed: 31534497
pmcid: 6735397
Uhlén, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419. https://doi.org/10.1126/science.1260419 (2015).
doi: 10.1126/science.1260419
pubmed: 25613900
Dyachok, J., Earnest, S., Iturraran, E. N., Cobb, M. H. & Ross, E. M. Amino acids regulate mTORC1 by an obligate two-step mechanism. J. Biol. Chem. 291, 22414–22426. https://doi.org/10.1074/jbc.M116.732511 (2016).
doi: 10.1074/jbc.M116.732511
pubmed: 27587390
pmcid: 5077182
Panwar, V. et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct. Target Ther. 8, 375. https://doi.org/10.1038/s41392-023-01608-z (2023).
doi: 10.1038/s41392-023-01608-z
pubmed: 37779156
pmcid: 10543444
Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22. https://doi.org/10.1016/j.ccr.2007.05.008 (2007).
doi: 10.1016/j.ccr.2007.05.008
pubmed: 17613433
Zhang, Y. et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell 31, 820-832.e823. https://doi.org/10.1016/j.ccell.2017.04.013 (2017).
doi: 10.1016/j.ccell.2017.04.013
pubmed: 28528867
pmcid: 5502825
Wan, Z., Wang, Y., Li, C. & Zheng, D. SLC14A1 is a new biomarker in renal cancer. Clin. Transl. Oncol. 25, 2607–2623. https://doi.org/10.1007/s12094-023-03140-6 (2023).
doi: 10.1007/s12094-023-03140-6
pubmed: 37004669
Li, C. et al. Clinical significance of the reduction of UT-B expression in urothelial carcinoma of the bladder. Pathol. Res. Pract. 210, 799–803. https://doi.org/10.1016/j.prp.2014.09.012 (2014).
doi: 10.1016/j.prp.2014.09.012
pubmed: 25445116
Hou, R., Kong, X., Yang, B., Xie, Y. & Chen, G. SLC14A1: A novel target for human urothelial cancer. Clin. Transl. Oncol. 19, 1438–1446. https://doi.org/10.1007/s12094-017-1693-3 (2017).
doi: 10.1007/s12094-017-1693-3
pubmed: 28589430
pmcid: 5700210
Zhou, Y. et al. Downregulation of SLC14A1 expression indicates poor prognosis and promotes the progression of non-small cell lung cancer. Ann. Clin. Lab. Sci. 52, 753–762 (2022).
pubmed: 36261188
Li, J. et al. Urea transporter B downregulates polyamines levels in melanoma B16 cells via p53 activation. Biochim. Biophys. Acta Mol. Cell. Res. 1869, 119236. https://doi.org/10.1016/j.bbamcr.2022.119236 (2022).
doi: 10.1016/j.bbamcr.2022.119236
pubmed: 35143901