Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

Wang, Yanhong; Wang, Jiaqi; Yang, Lingrong; Qiu, Liqing; Hua, Yuhui; Wu, Shixiu; Zeng, Su; Yu, Lushan; Zheng, Xiaoli

doi:10.1038/s41419-021-03814-5

Cited by 11 publications

(10 citation statements)

References 64 publications

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“…A Chinese cohort GWAS comprising 3,406 cases of bladder cancer and 4,645 controls identified a new susceptibility locus for BCa in the intron of CWC27 (rs2042329) [ 11 ]. SCL15A1, also called PEPT1, was reported to be a highly expressed drug target protein in many different human cancers, including colorectal cancer [ 12 ], gastric cancer [ 13 ], hepatocarcinoma cells [ 14 ], and prostate cancer [ 15 ]. SCL15A1 is one of the important molecules during cancer development.…”

Section: Introductionmentioning

confidence: 99%

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

Guo

2022

BioMed Research International

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Bladder cancer (BCa) is an increasingly severe clinical and public health issue. Therefore, we aim to investigate BCa susceptibility loci in the Chinese population. In this study, 487 BCa patients and 563 controls were recruited from the First Affiliated Hospital of China Medical University from July 2015 to September 2020. A total of ten single-nucleotide polymorphisms (SNPs) in solute carrier family 15 member 1 (SLC15A1), CWC27 spliceosome associated cyclophilin (CWC27), or UDP glucuronosyltransferase family 1 member A3 (UGT1A3) genes were genotyped. The associations between the candidate SNPs and BCa were analyzed using genotype and haplotype analysis. The results demonstrated that Rs4646227 of SLC15A1 has a significant association with BCa. The patients with CG (OR =2.513, p < 0.05 ) and GG (OR =2.859, p < 0.05 ) genotypes had an increasing risk of BCa compared with the CC genotype. For the CWC27 gene, genotypic frequency analysis revealed that the GT or TT genotype of rs2042329 and the CT or TT genotype of rs1870437 were more frequent in BCa patients than those in the control group, indicating that these genotypes were associated with a higher risk of BCa (all p < 0.05 ). Haplotypes of SLC15A1, UGT1A3, and CWC27 genes found that the C-C-C haplotype of SLC15A1 was associated with a lower risk of BCa while the C-G-C haplotype was associated with a higher risk. For the UGT1A3 gene, a moderate protective effect was observed with the most frequent T-T-C haplotype, and for the CWC27 gene, most of the haplotypes showed no association with BCa, except the G-G-C-T haplotype (order of SNPs: rs2042329-rs7735338-rs1870437-rs2278351, OR =0.81, p =0.038). In sum, this study indicated that rs2042329 and rs1870437 in the CWC27 gene and rs4646227 in the SLC15A1 gene are independent indicators for BCa risk in Chinese people. Further large-scale studies are required to validate these findings. Also, this study provided the theoretical basis for developing new therapeutic drug targeting of BCa.

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Section: Introductionmentioning

confidence: 99%

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

Guo

2022

BioMed Research International

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“…SLC4A4 and SLC9A3 can transport H + and HCO 3 – , respectively, thus affecting tumor cell PH regulation. SLC15A1 has a significant effect on intestinal peptide transport affects intestinal diseases. ,− SLC38A3 is known for its involvement in amino acid transport and is extensively documented in neurological disorders. − Previous studies have explored the role of SLC38A3 in glutamine metabolism and its effect on tumor progression. Our study identified SLC38A3 as a novel prognostic marker gene in CRC, and the knockdown of SLC38A3 in HCT cells inhibited CRC cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

SLC38A3 Promotes the Proliferation and Migration of Tumor Cells and Predicts Poor Prognosis in Colorectal Cancer

Zhang,

Huang,

Zeng

et al. 2024

ACS Omega

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Previous studies have revealed that abnormal expressions of membrane transporters were associated with colorectal cancer (CRC). We herein performed a comprehensive bioinformatics analysis to identify the key transporter protein-related genes involved in CRC and potential mechanisms. Differentially expressed transporter protein-related genes (DE-TPRGs) were identified from CRC and normal samples using The Cancer Genome Atlas database. SLC38A3 expression was validated by immunohistochemistry and RT-qPCR, and the potential mechanism was explored. A total of 63 DE-TPRGs (29 up-regulated and 34 down-regulated) were screened. Inside, ABCC2, ABCG2, SLC4A4, SLC9A3, SLC15A1, and SLC38A3 were identified as hub genes. SLC38A3 is indeed upregulated in colorectal cancer patients. Furthermore, we found that knockdown of SLC38A3 inhibited the proliferation and migration of HCT116 cells, and Hsp70 ATPase activator could rescue it. Overall, SLC38A3 is a novel potential biomarker involved in CRC progression and promotes the proliferation and migration of tumor cells by positively regulating the function of Hsp70.

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“…There is little understanding of epigenetic regulation of PEPTs until very recently. Wang et al reported a suppressed expression of SLC15A1 (PEPT1) in colon cancer due to DNA methylation and histone deacetylation (Wang et al, 2021a). DNA methyltransferase 1 was characterized as the primary determinant of the hypermethylation of SLC15A1 proximal promoter.…”

Section: Transcriptional Regulation Of Peptsmentioning

confidence: 99%

Transcriptional Regulation of Solute Carrier Drug Transporters

Zhou

Shu

2022

Drug Metab Dispos

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Facilitated transport is necessitated for large size, charged, and/or hydrophilic drugs to move across the membrane. The drug transporters in the solute carrier (SLC) superfamily, mainly including organic anion-transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), peptide transporters (PEPTs), and multidrug and toxin extrusion proteins (MATEs), are critical facilitators of drug transport and distribution in human body. The expression of these SLC drug transporters is found in tissues throughout the body, with high abundance in the epithelial cells of major organs for drug disposition, such as intestine, liver, and kidney. These SLC drug transporters are clinically important in drug absorption, metabolism, distribution, and excretion. The mechanisms underlying their regulation have been revealing in recent years. Epigenetic and nuclear receptor-mediated transcriptional regulation of SLC drug transporters have particularly attracted much attention. This review focuses on the transcriptional regulation of major SLC drug transporter genes. Revealing the mechanisms underlying the transcription of those critical drug transporters will help us understand pharmacokinetics and pharmacodynamics, ultimately improving drug therapeutic effectiveness while minimizing drug toxicity.

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Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

Cited by 11 publications

References 64 publications

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

SLC38A3 Promotes the Proliferation and Migration of Tumor Cells and Predicts Poor Prognosis in Colorectal Cancer

Transcriptional Regulation of Solute Carrier Drug Transporters

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