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RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

ABSTRACT: The invasiveness of pancreatic cancer and its resistance to anticancer drugs define its malignant potential, and are considered to affect the peritumoral microenvironment. Cancer cells with resistance to gemcitabine exposed to external signals induced by anticancer drugs may enhance their malignant transformation. Ribonucleotide reductase large subunit M1 (RRM1), an enzyme in the DNA synthesis pathway, is upregulated during gemcitabine resistance, and its expression is associated with worse prognosis for pancreatic cancer. However, the biological function of RRM1 is unclear. In the present study, it was demonstrated that histone acetylation is involved in the regulatory mechanism related to the acquisition of gemcitabine resistance and subsequent RRM1 upregulation. The current in vitro study indicated that RRM1 expression is critical for the migratory and invasive potential of pancreatic cancer cells. Furthermore, a comprehensive RNA sequencing analysis showed that activated RRM1 induced marked changes in the expression levels of extracellular matrix‑related genes, including N‑cadherin, tenascin‑C and COL11A. RRM1 activation also promoted extracellular matrix remodeling and mesenchymal features, which enhanced the migratory invasiveness and malignant potential of pancreatic cancer cells. The present results demonstrated that RRM1 has a critical role in the biological gene program that regulates the extracellular matrix, which promotes the aggressive malignant phenotype of pancreatic cancer.

SUBMITTER: Ono H

PROVIDER: S-EPMC10019754 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

Ono Hiroaki H Murase Yoshiki Y Yamashita Hironari H Kato Tomotaka T Asano Daisuke D Ishikawa Yoshiya Y Watanabe Shuichi S Ueda Hiroki H Akahoshi Keiichi K Ogawa Kosuke K Kudo Atsushi A Akiyama Yoshimitsu Y Tanaka Shinji S Tanabe Minoru M

International journal of oncology 20230303 4

The invasiveness of pancreatic cancer and its resistance to anticancer drugs define its malignant potential, and are considered to affect the peritumoral microenvironment. Cancer cells with resistance to gemcitabine exposed to external signals induced by anticancer drugs may enhance their malignant transformation. Ribonucleotide reductase large subunit M1 (RRM1), an enzyme in the DNA synthesis pathway, is upregulated during gemcitabine resistance, and its expression is associated with worse prog ...[more]

PMID: 36866763

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a poor prognosis, and resistance to gemcitabine, a frontline chemotherapeutic agent, poses a significant challenge to effective treatment. Unraveling the molecular underpinnings of gemcitabine resistance is essential for devising novel therapeutic strategies. Here we derived gemcitabine-resistant and parental pancreatic cancer cell lines from KPC mouse models of PDAC. Employing a multi-omics approach, we integrated RNA-seq, ATAC-seq, and ChIP-seq analyses to characterize the genome-wide alterations in gene transcription, chromatin accessibility, histone modifications, and transcription factor (TF) binding in resistant cells. High-throughput chromatin conformation capture (Hi-C) was used to explore 3D chromatin remodeling. Our analyses identified differentially expressed genes (DEGs) critical for gemcitabine metabolism and resistance, notably Rrm1 and Cdadc1. We observed the upregulation of NF-kB, p53, and MAPK pathways, and the downregulation of mTORC1, MYC targets, and reactive oxygen species pathways. Differentially accessible regions (DARs) showed a significant positive correlation with the expression patterns of DEGs and histone mark H3K27 acetylation. Motif enrichment analyses revealed that TFs from the AP-1, Fox, and Hox families were significantly enriched at DARs, underscoring Foxa1 as a pivotal regulator of resistance-associated genes. We discovered that 3D chromatin reorganization, particularly the enhancement of enhancer-promoter interactions involving super-enhancer (SE) reprogramming mediated by Foxa1 and Ctcf/Smc3, drives the expression of critical resistance genes. Targeting Foxa1 or disrupting SE-associated transcription using JQ1, a bromodomain inhibitor, effectively inhibited resistant cell proliferation and enhanced gemcitabine sensitivity. In summary, this study elucidates the role of TF-mediated chromatin remodeling in gemcitabine resistance and suggests that targeting super-enhancers could be a promising therapeutic strategy to overcome resistance in PDAC, potentially revolutionizing drug therapy for this disease.

Dataset Information

RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

Publications

RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

Similar Datasets

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