Epigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia

Changhu Lee, Min Kim, Chanho Park, Woobeen Jo, Jeong Kon Seo, Sahee Kim, Jiyoung Oh, Chu-Sook Kim, Han Suk Ryu, Kyung-Hun Lee and Jiyoung Park ()
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Changhu Lee: Ulsan National Institute of Science and Technology
Min Kim: Ulsan National Institute of Science and Technology
Chanho Park: Ulsan National Institute of Science and Technology
Woobeen Jo: Ulsan National Institute of Science and Technology
Jeong Kon Seo: Ulsan National Institute of Science and Technology
Sahee Kim: Ulsan National Institute of Science and Technology
Jiyoung Oh: Ulsan National Institute of Science and Technology
Chu-Sook Kim: Ulsan National Institute of Science and Technology
Han Suk Ryu: Seoul National University Hospital, Seoul National University College of Medicine
Kyung-Hun Lee: Seoul National University
Jiyoung Park: Ulsan National Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36179-8

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