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Nat. Commun., 2023 Jan 27;14(1):439 | https://doi.org/10.1038/s41467-023-36179-8 Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia

Changhu Lee¹, Min Kim¹, Chanho Park¹, Woobeen Jo¹, Jeong Kon Seo², Sahee Kim¹, Jiyoung Oh¹, Chu-Sook Kim¹, Han Suk Ryu³, Kyung-Hun Lee⁴ & Jiyoung Park¹

¹Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
²UNIST Central Research Facility, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
³Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁴Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.

Corresponding author : Correspondence to Jiyoung Park.

Abstract

Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, we show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where recombination signal binding protein for immunoglobulin kappa J region (RBPJ), E1A binding protein p300 (P300), and SET domain containing 1 A (SETD1A) are recruited to upregulate Nrg1 expression. Deletions in RBPJ-binding sites causes hyperglycemia-controlled Nrg1 levels to be downregulated, resulting in decreased tumor growth in vitro and in vivo. Mice with modest-temporary hyperglycemia, induced by low-dose short-exposure streptozotocin, display accelerated tumor growth and lapatinib resistance, whereas combining lapatinib with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S42 phenylglycine t-butyl ester (DAPT) ameliorates tumor growth under these modest hyperglycemic conditions by inhibiting NOTCH and EGFR superfamilies. NOTCH activity is correlated with NRG1 levels, and high NRG1 levels predicts poor outcomes, particularly in HER2-positive breast cancer patients. Our findings highlight the hyperglycemia-linked epigenetic modulation of NRG1 as a potential therapeutic strategy for treating breast cancer patients with diabetes.

논문정보

형식Research article
게재일2023년 01월 (BRIC 등록일 2023-03-09)
연구진국내 연구진
분야 생명과학 > 분자생물학

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