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NNMT switches the proangiogenic phenotype of cancer-associated fibroblasts via epigenetically regulating ETS2/VEGFA axis.
Wang, Xinmiao; Zhao, Hui; Luo, Xinyue; Chen, Yang; Shi, Congyu; Wang, Yifan; Bai, Junqiang; Shao, Zhe; Shang, Zhengjun.
Afiliação
  • Wang X; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Zhao H; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Luo X; Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology-Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Chen Y; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Shi C; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Wang Y; Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Bai J; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Shao Z; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
  • Shang Z; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Oncogene ; 43(35): 2647-2660, 2024 Aug.
Article em En | MEDLINE | ID: mdl-39069579
ABSTRACT
Cancer-associated fibroblasts (CAFs) are known to promote angiogenesis in oral squamous cell carcinoma (OSCC). However, the epigenetic mechanisms through which CAFs facilitate angiogenesis within the tumor microenvironment are still poorly characterized. Nicotinamide N'-methyltransferase (NNMT), a member of the N-methyltransferase family, was found to be a key molecule in the activation of CAFs. This study shows that NNMT in fibroblasts contributes to angiogenesis and tumor growth through an epigenetic reprogramming-ETS2-VEGFA signaling axis in OSCC. Single-cell RNA Sequencing (scRNA-seq) analysis suggests that NNMT is mainly highly expressed in fibroblasts of head and neck squamous cell carcinoma (HNSCC). Moreover, analysis of the TCGA database and multiple immunohistochemical staining of clinical samples also identified a positive correlation between NNMT and tumor angiogenesis. This research further employed an assembled organoid model and a fibroblast-endothelial cell co-culture model to authenticate the proangiogenic ability of NNMT. At the molecular level, high expression of NNMT in CAFs was found to promote ETS2 expression by regulating H3K27 methylation level through mediating methylation deposition. Furthermore, ETS2 was verified to be an activating transcription factor of VEGFA in this study. Collectively, our findings delineate an epigenetic molecular regulatory network of angiogenesis and provide a theoretical basis for exploring new targets and clinical strategy in OSCC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Bucais / Regulação Neoplásica da Expressão Gênica / Fator A de Crescimento do Endotélio Vascular / Epigênese Genética / Nicotinamida N-Metiltransferase / Proteína Proto-Oncogênica c-ets-2 / Fibroblastos Associados a Câncer / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neovascularização Patológica Limite: Animals / Humans Idioma: En Revista: Oncogene Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Bucais / Regulação Neoplásica da Expressão Gênica / Fator A de Crescimento do Endotélio Vascular / Epigênese Genética / Nicotinamida N-Metiltransferase / Proteína Proto-Oncogênica c-ets-2 / Fibroblastos Associados a Câncer / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neovascularização Patológica Limite: Animals / Humans Idioma: En Revista: Oncogene Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido