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Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer.

ABSTRACT: Upregulation of the H3K4me3 demethylase JARID1B is linked to acquisition of aggressive, stem cell-like features by many cancer types. However, the utility of emerging JARID1 family inhibitors remains uncertain, in part because JARID1B's functions in normal development and malignancy are diverse and highly context-specific. In this study, responses of oral squamous cell carcinomas (OSCCs) to catalytic inhibition of JARID1B were assessed using CPI-455, the first tool compound with true JARID1 family selectivity. CPI-455 attenuated clonal sphere and tumor formation by stem-like cells that highly express JARID1B while also depleting the CD44-positive and Aldefluor-high fractions conventionally used to designate OSCC stem cells. Silencing JARID1B abrogated CPI-455's effects on sphere formation, supporting that the drug acted through this isoform. To further delineate CPI-455's capacity to block JARID1B's functions, its biologic effects were compared against those indicated by pathway analysis of the transcriptional profile produced by JARID1B knockdown. Downregulation of multiple gene sets related to stem cell function was consistent with the drug's observed actions. However, strong E-Cadherin upregulation seen upon silencing JARID1B surprisingly could not be reproduced using CPI-455. Expressing a demethylase-inactive mutant of JARID1B demonstrated suppression of this transcript to be demethylase-independent, and the capacity of mutant JARID1B but not CPI-455 to modulate invasion provided a functional correlate of this finding. These results show that JARID1B catalytic inhibition effectively targets some stem cell-like features of malignancy but also reveal demethylase-independent actions refractory to inhibition. Future application of JARID1 inhibitors in combinatorial use for cancer therapy may be guided by these findings.

SUBMITTER: Facompre ND

PROVIDER: S-EPMC5823649 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer.

Facompre Nicole D ND Harmeyer Kayla M KM Sahu Varun V Gimotty Phyllis A PA Rustgi Anil K AK Nakagawa Hiroshi H Basu Devraj D

Oncotarget 20171215 10

Upregulation of the H3K4me3 demethylase JARID1B is linked to acquisition of aggressive, stem cell-like features by many cancer types. However, the utility of emerging JARID1 family inhibitors remains uncertain, in part because JARID1B's functions in normal development and malignancy are diverse and highly context-specific. In this study, responses of oral squamous cell carcinomas (OSCCs) to catalytic inhibition of JARID1B were assessed using CPI-455, the first tool compound with true JARID1 fami ...[more]

PMID: 29507668

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Project description:BACKGROUND:Discoidin domain receptor-1 (DDR1) tyrosine kinase is highly expressed in a variety of human cancers and involved in various steps of tumorigenesis. However, the precise mechanisms underlying the abnormal expression of DDR1 in oral squamous cell carcinoma (OSCC) has not been well investigated. METHODS:The expression of DDR1 on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-486-3p and DDR1 were accessed by MTT and Annexin V analyses using gain- and loss-of-function approaches. Chromatin immunoprecipitation (ChIP) and methylation specific PCR (MSP) were performed to explore the molecular mechanisms by arecoline treatment. RESULTS:Here, we reported that DDR1 was significantly upregulated in OSCC tissues and its levels were inversely correlated with miR-486-3p expression. The experimental results in vitro confirmed that miR-486-3p decreased DDR1 expression by targeting the 3'-UTR of DDR1 mRNA. Overexpression of miR-486-3p led to growth inhibition and apoptosis induction with a similar function by knockdown of DDR1. Aberrant methylation of ANK1 promoter was a highly prevalent in OSCC and contributes to oral carcinogenesis by epigenetic silencing of ANK1 and miR-486-3p. We found that miR-486-3p can be transcriptionally co-regulated with its host gene ANK1 through epigenetic repression. DNA methylation inhibitor treatment re-expressed ANK1 and miR-486-3p. Importantly, arecoline, a major betel nut alkaloid, recruited DNMT3B binding to ANK1 promoter for DNA methylation and then attenuated the expression of miR-486-3p in OSCC. CONCLUSION:This study was the first to demonstrate that betel nut alkaloid may recruit DNMT3B to regulate miR-486-3p/DDR1 axis in oral cancer andmiR-486-3p and DDR1 may serve as potential therapeutic targets of oral cancer.

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Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer.

Publications

Targeting JARID1B's demethylase activity blocks a subset of its functions in oral cancer.

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