Dataset Information

The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis.

ABSTRACT: PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression. Inhibition of DNA methyltransferases (DNMTs) leads to elevated hyaluronan levels; however, whether DNMT inhibitors control PH20 remains unclear. Here, we report that the DNMT1 inhibitor, decitabine, suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1 (PAS1). PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1. The interaction between PAS1 and vigilin maintains the stability of PAS1. Meanwhile, PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20, resulting in its silencing. Functionally, PAS1 inhibits breast cancer growth and metastasis, at least partially, by suppressing PH20. Combination therapy of decitabine and PAS1-30nt-RNA, which directly binds to SUV39H1, effectively blocked breast cancer growth and metastasis in mice. Taken together, DNMT1, PAS1, and PH20 comprise a regulatory axis to control breast cancer growth and metastasis. These findings reveal that the DNMT1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.

SUBMITTER: Fu Y

PROVIDER: S-EPMC8934873 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis.

Fu Yenan Y Zhang Xi X Liu Xiao X Wang Peng P Chu Wenhui W Zhao Wei W Wang Yunling Y Zhou Guangbiao G Yu Yu Y Zhang Hongquan H

Signal transduction and targeted therapy 20220321 1

PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression. Inhibition of DNA methyltransferases (DNMTs) leads to elevated hyaluronan levels; however, whether DNMT inhibitors control PH20 remains unclear. Here, we report that the DNMT1 inhibitor, decitabine, suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1 (PAS1). PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone ...[more]

PMID: 35307730

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Project description:Background & aimsIntrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and inter-tumoral molecular heterogeneity, partly due to its diverse cellular origins. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development.MethodsExpression of ICC driver genes in human diseased livers at risk for ICC development were examined. The sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SRY-box transcription factor 9 (SOX9) and yes-associated protein 1 (YAP1) in HC-driven ICC. We identified DNA methyltransferase 1 (DNMT1) as a YAP1 target, which was validated by loss- and gain-of-function studies, and its mechanism addressed by chromatin immunoprecipitation sequencing.ResultsCo-expression of AKT and Notch intracellular domain (NICD)/YAP1 in HC yielded ICC that represents 13% to 29% of clinical ICC. NICD independently regulates SOX9 and YAP1 and deletion of either, significantly delays ICC development. Yap1 or TEAD inhibition, but not Sox9 deletion, impairs HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate switch through the repression of HC-specific genes regulated by master regulators for HC differentiation, including hepatocyte nuclear factor 4 alpha, hepatocyte nuclear factor 1 alpha, and CCAAT/enhancer-binding protein alpha/beta. DNMT1 loss prevented NOTCH/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in a subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development.ConclusionWe identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-to-BEC/ICC conversion, which may be relevant in cholestasis-to-ICC pathogenesis in the clinic.

Dataset Information

The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis.

Publications

The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis.

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