Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity

Wu, Xingcheng; Zuo, Yuzhi; Song, Xiaolei; Zhou, Zhien; Xiao, Yu; Luo, Dao-Sheng; Yan, Weigang; Zhao, Shan‐Chao

doi:10.1186/s12967-022-03291-0

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…Similar to PGM3 in colorectal cancer [ 166 ], the upregulation of UAP1 in liver cancer correlates with increased O -GlcNAcylation and overexpression of β-catenin [ 172 ]. UAPL1, a paralog of UAP1 that shares 59% sequence identity, is also upregulated in tumors such as hepatocellular carcinoma (HCC) and prostate and breast cancer [ 173 , 174 , 175 ]. Although UAPL1 directly interacts with OGT and, like UAP1, is required for OGT-mediated protein O -GlcNAcylation, it has only a minor role in UDP-GlcNAc synthesis.…”

Section: Hbp In Health and Diseasementioning

confidence: 99%

The Hexosamine Biosynthesis Pathway: Regulation and Function

Paneque

Fortus

Zheng

et al. 2023

Genes

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The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.

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Section: Hbp In Health and Diseasementioning

confidence: 99%

The Hexosamine Biosynthesis Pathway: Regulation and Function

Paneque

Fortus

Zheng

et al. 2023

Genes

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“…Accumulating evidence suggests that CDCA8 dysregulation is observed in many cancers and is essential for cell survival and metastasis for gastric [5], kidney, colorectal [6], lung [7], and breast cancers [8]. As for the mechanism of CDCA8 overexpression, UAP1L1 is identified as a critical factor for CDCA8 expression, and promotes cell growth, migration, invasion, and apoptosis in prostate cancer [9]. KIF18 was found to bind to the promoter region of CDCA8 and enhance CDCA8 expression, as well as increase cell proliferation capacity in pancreatic cancer [10].…”

Section: Inductionmentioning

confidence: 99%

CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway

Chen

Jiang

et al. 2023

Exp Hematol Oncol

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Background Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors. Cell division cycle associated 8 (CDCA8) is an important multifactorial regulator in cancers. However, its up and downstream targets and effects in HCC are still unclear. Methods A comprehensive bioinformatics analysis was performed using The Cancer Genome Atlas dataset (TCGA) to explore novel core oncogenes. We quantified CDCA8 levels in HCC tumors using qRT-PCR. HCC cell’s proliferative, migratory, and invasive abilities were detected using a Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2′-deoxyuridine (EdU) assay, clone formation, and a Transwell assay. An orthotopic tumor model and tail vein model were constructed to determine the effects of CDCA8 inhibition in vivo. The mechanism underlying CDCA8 was investigated using RNA sequencing. The prognostic value of CDCA8 was assessed with immunohistochemical staining of the tissue microarrays. Results CDCA8 was identified as a novel oncogene during HCC development. The high expression of CDCA8 was an independent predictor for worse HCC outcomes both in publicly available datasets and in our cohort. We found that CDCA8 knockdown inhibited HCC cell proliferation, colony formation, and migration by suppressing the MEK/ERK pathway in vitro. Moreover, CDCA8 deficiency significantly inhibited tumorigenesis and metastasis. Next-generation sequencing and laboratory validation showed that CDCA8 silencing inhibited the expression of TPM3, NECAP2, and USP13. Furthermore, NA-YA overexpression upregulated the expression of CDCA8. CDCA8 knockdown could attenuate NF-YA-mediated cell invasion in vitro. The expression of NF-YA alone or in combined with CDCA8 were validated as significant independent risk factors for patient survival. Conclusion Our findings revealed that the expression of CDCA8 alone or in combined with NF-YA contributed to cancer progression, and could serve as novel potential therapeutic targets for HCC patients.

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“…While both software are easy to use with detailed tutorials, GSEA has the advantage of being free of fees, while IPA requires a subscription fee. IPA has been extensively used in PCa to study canonical pathways and molecule interactions in different disease states [354][355][356][357][358][359].…”

Section: Enrichment Analysismentioning

confidence: 99%

Lineage Plasticity and Stemness Phenotypes in Prostate Cancer: Harnessing the Power of Integrated “Omics” Approaches to Explore Measurable Metrics

Logotheti,

Papadaki,

Zolota

et al. 2023

Cancers

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Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients.

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Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity

Cited by 6 publications

References 30 publications

The Hexosamine Biosynthesis Pathway: Regulation and Function

The Hexosamine Biosynthesis Pathway: Regulation and Function

CDCA8 induced by NF-YA promotes hepatocellular carcinoma progression by regulating the MEK/ERK pathway

Lineage Plasticity and Stemness Phenotypes in Prostate Cancer: Harnessing the Power of Integrated “Omics” Approaches to Explore Measurable Metrics

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