CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A

Sep 21, 2026

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Coactivator-associated arginine methyltransferase 1 (CARM1) promotes development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer, while its role in triple-negative breast cancer (TNBC) remained unclear. The study reports that CARM1 enhances proliferation, epithelial–mesenchymal transition, and stemness in TNBC. Genome-wide analysis shows CARM1 is recruited by hypoxia-inducible factor-1 subunit alpha (HIF1A), occupying promoters of CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, and SIX1, thereby regulating proliferation and invasion. Physical association and direct interaction between CARM1 and HIF1A were demonstrated, and ellagic acid suppresses TNBC via inhibition of CDK4 expression, offering potential therapy directions.

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CategoryHealthcare

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Abstract

Introduction

Protein & Cell Protein Cell, 2024, 15, 744–765 [https://doi.org/10.1093/procel/pwae010](https://doi.org/10.1093/procel/pwae010) Advance access publication 13 March 2024 & Research Article Protein Cell Research Article CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A Dandan Feng1,2,‡, Jie Gao3,‡,, Ruiqiong Liu3,4,‡,, Wei Liu2, Tianyang Gao2, Yunkai Yang1, Die Zhang1, Tianshu Yang5, Xin Yin5, Hefen Yu5,, Wei Huang5,*,, Yan Wang1,2,5,*, 1Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 2Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China 3Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China 4Department of Cancer Center, The Second Hospital of Shandong University, Jinan 250033, China 5Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China ‡These authors contributed equally to this work. * [Correspondence:](Correspondence: weihuang@ccmu.edu.cn)[ weihuang@ccmu.edu.cn](Correspondence: weihuang@ccmu.edu.cn) (W. Huang), [yanwang@cicams.ac.cn](yanwang@cicams.ac.cn) (Y. Wang) Abstract Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function of CARM1 in triple-negative breast cancer (TNBC) is still unclear and requires further exploration. Here, we report that CARM1 promotes proliferation, epithelial–mesenchymal transition, and stemness in TNBC. CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression. Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxiainducible factor-1 subunit alpha (HIF1A) and occupy the promoters of CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, and SIX1 critically involved in cell cycle, HIF-1 signaling pathway, Wnt signaling pathway, VEGF signaling pathway, thereby modulating the proliferation and invasion ofTNBC cells. We demonstrated that CARM1 is physically associated with and directly interacts with HIF1A. Moreover, we found that ellagic acid, an inhibitor of CARM1, can suppress the proliferation and invasion ofTNBC by directly inhibiting CDK4 expression. Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor, which may provide new ideas and drugs for cancer therapy. Keywords CARM1, HIF1A, CDK4, ellagic acid, TNBC Introduction For women, breast cancer alone accounting for 31% of female cancers. Female breast cancer incidence rates have been slowly increasing (Siegel et al., 2023). Among different subtypes of breast cancer, triple-negative breast cancer (TNBC) with negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is more malignant, easy to disseminate, and has no effective treatment and poor prognosis (Garrido-Castro et al. , 2019; Kalimutho et al. , 2015) . Arginine methylation is reported as a key posttranslational modification (PTM) and is involved in various cellular processes, such as mRNA splicing, DNA damage signaling, transcription, and cell signaling (Blanc and Richard, 2017 ; Jarrold and Davies, 2019) . Protein arginine methyltransferases (PRMTs) can catalyze the formation of methylated arginine and S-adenosylhomocysteine. Thus far, three types of modified arginine have been identified: monomethylatedarginine (MMA), asymmetric dimethylarginine (ADMA), Received 11 July

FAQs

What does the study identify as CARM1’s role in triple-negative breast cancer (TNBC)?

CARM1 promotes TNBC proliferation, epithelial–mesenchymal transition, and stemness.

How is CARM1 recruited and what genes does it regulate according to genome-wide analysis?

CARM1 is recruited by HIF1A and occupies promoters of CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, and SIX1, modulating pathways linked to TNBC proliferation and invasion.

How does ellagic acid affect TNBC in this research?

Ellagic acid suppresses TNBC proliferation and invasion by directly inhibiting CDK4 expression.

Sep 21, 2026

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