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Global Lactylation Profiling Reveals Lactate-Driven Regulatory Mechanisms Promoting Tumor Progression in Oral Squamous Cell Carcinoma

ABSTRACT: Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Six pairs of OSCC tissues underwent lactylation modification sequencing. 2,765 lactylation modification sites on 1,033 proteins were identified in OSCC, indicating its widespread presence. These modifications influenced metabolic activities, molecular synthesis, and transport.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Tongue Cancer Cell

SUBMITTER: Fengyang Jing

LAB HEAD: Fengyang Jing

PROVIDER: PXD047535 | Pride | 2024-08-23

REPOSITORIES: Pride

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			Action	DRS
	XA00303B2LPLa_NAT16_E2_1_17773.d.zip	Other
	XA00303B2LPLa_NAT3_C8_1_17753.d.zip	Other
	XA00303B2LPLa_NAT4_D2_1_17757.d.zip	Other
	XA00303B2LPLa_NAT5_D4_1_17761.d.zip	Other
	XA00303B2LPLa_NAT7_D6_1_17765.d.zip	Other

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Global Lactylation Profiling Reveals Lactate-Driven Regulatory Mechanisms Promoting Tumor Progression in Oral Carcinoma

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Project description:In order to aid the development of patient-tailored diagnostics and therapeutics, we attempted to identify a genetic signature associated with disease prognosis in OSCC. A genome-wide analysis of transcription with the Affymetrix GeneChip Human Gene 1.0 ST Array was conducted. In this dataset, we include the expression data obtained from 57 specimens from patients with OSCC and 22 oral tissues from normal persons. 79 samples were analyzed. We compared gene expression levels between patients with and without OSCC. In addition, among 57 patients with OSCC, we also compared the expression levels between patients with and without amplicons scattered in chromosome 8q22.2~24.3.

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Project description:Oral cavity cancer is one of the most common cancer worldwide and oral cavity squamous cell carcinoma (OSCC) accounts for up to 90 percent of oral cancers. In Taiwan, OSCC is the fifth most common malignancy of male and causes more than 250 deaths per year. The poor outcome of OSCC patients is principally ascribed to the fact that this disease is often advanced at the time of diagnosis, suggesting that early detection and prevention of OSCC are urgently needed to reduce the cancer burden. Analysis of cancer-related body fluids is one of promising approaches to identify cancer-related molecules and biomarker candidates. To identify salivary biomarkers of OSCC, salivary samples of OSCC patients, individuals with oral potentially malignant disorders (OPMD), and healthy volunteers were collected. With isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry (MS) analysis, 1838 proteins were identified. The levels of 102 proteins are found to be elevated in the saliva samples of OSCC patients compared to that of OPMD and healthy groups. To improve the feasibility of biomarkers, we used a two-phase verification to measure these candidates. Among them, salivary levels of AHSG, CFH, FGA, and SERPINA1 were determined to be significantly higher in the OSCC patients than in the healthy or in the OPMD group with both of MRM-MS and ELISA. Furthermore, the levels of these proteins were highly related to tumor size, lymph-node metastasis, and cancer stages. The results of this study not only provides a powerful strategy for verification of biomarker candidates, but also suggested that AHSG, CFH, FGA, and SERPINA1 could act as salivary biomarkers for OSCC detection.

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Project description:MicroRNAs (miRNAs) participate in many biological processes and have emerged as key players in carcinogenesis. In order to identify changes in miRNAs specific for betelquid-associated oral squamous cell carcinoma (OSCC), we investigated the expression profiles of 858 miRNAs in a panel of 40 pairs of OSCC specimens and their matched non-tumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared to the matched tissue. Among these miRNAs, 19 downregulated miRNAs located in the chromosome 14q32.2 miRNA cluster region were analyzed. This miRNA cluster resides within a parentally imprinted region known to be important in development and growth. The re-expression of miR-329 and miR-410from this cluster significantly reduced OSCC cell proliferation and invasion and downregulated Wnt-7b, an activator of the Wnt/b-catenin pathway. Furthermore, the expression of those 2 miRNAs was restored by 5-aza-2′-deoxycytidine treatment and the expression levels of the 2 miRNAs were inversely correlated with the hypermethylation of the Meg-3 promoter in OSCC cells. Specifically, arecoline, a major betel nut alkaloid, reduces miR-329 and miR-410 expression. Our results thus provide a novel molecular insight into how betel quid may contribute to oral carcinogenesis through the epigenetic silencing of tumor suppressor miRNAs targeting the Wnt/b-catenin signaling pathway. Total RNA was obtained from 40 pairs of OSCC patients with tumor specimens and their adjacent non-tumorous epithelia.

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Global Lactylation Profiling Reveals Lactate-Driven Regulatory Mechanisms Promoting Tumor Progression in Oral Squamous Cell Carcinoma [RNA-seq]

Project description:Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Oral squamous cell carcinoma cell lines, before and after lactate treatment, underwent CUT&TAG, ATAC, and transcriptomic sequencing. ChIP-qPCR and RT-qPCR validated results in OSCC tissues. Integrated analysis identified 217 genes with increased expression driven by lactylation in OSCC. Lactylation broadly impacted pathways in cancer, notably regulating PI3K/AKT and MAPK signaling. This pioneering study analyzes lactylation in OSCC, providing a global map of its regulation in oral squamous cell carcinoma from the perspective of chromatin-driven gene expression.

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