Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Llinàs-Arias, Pere (Institut d’Investigació Sanitària Illes Balears)
Ensenyat Méndez, Miquel (Cancer Epigenetics Laboratory. Health Research Institute of the Balearic Islands (IdISBa))
Íñiguez-Muñoz, Sandra (Cancer Epigenetics Laboratory. Health Research Institute of the Balearic Islands (IdISBa))
Orozco, Javier I. J (Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA)
Valdez, Betsy (Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.)
Salomon, Matthew P. (University of Southern California, Los Angeles, USA)
Matsuba, Chikako (University of Southern California, Los Angeles, USA)
Solivellas-Pieras, Maria (Cancer Epigenetics Laboratory. Health Research Institute of the Balearic Islands (IdISBa))
Bedoya-López, Andrés F. (Cancer Epigenetics Laboratory. Health Research Institute of the Balearic Islands (IdISBa))
Sesé, Borja (Cancer Epigenetics Laboratory. Health Research Institute of the Balearic Islands (IdISBa))
Mezger, Anja (Science for Life Laboratory, Solna, Sweden)
Ormestad, Mattias (Science for Life Laboratory, Solna, Sweden)
Unzueta, Fernando (Universitat de Barcelona)
Strand, Siri H. (Stanford University School of Medicine, Stanford, USA)
Boiko, Alexander D. (Samuel Oschin Comprehensive Cancer Institute, Los Angeles, USA)
Hwang, E.Shelley (Duke University School of Medicine, Durham, USA)
Cortés, Javier (Universidad Europea de Madrid)
DiNome, Maggie L. (Duke University School of Medicine, Durham, USA)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lupien, Mathieu (University of Toronto)
Marzese, Diego (Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa))

Date:	2023
Abstract:	Background: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results: We explored the clinical relevance of an insulator element located within the Chr11q22. 2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1. 57 [1. 06 − 2. 33]; p = 0. 023) and overall (HR = 2. 65 [1. 31 − 5. 37], p = 0. 005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0. 77, p < 0. 01). Conclusion: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.
Grants:	Instituto de Salud Carlos III PI22/01496 European Commission. Horizon 2020 824110
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	MMP1 ; MMP8 ; CTCF ; Insulator ; Chromatin ; Gene regulatory element ; Cis-regulatory element ; Breast cancer ; Invasion ; ATAC-seq ; RNA-seq ; Hi-C
Published in:	Molecular cancer, Vol. 22 Núm. 1 (november 2023) , ISSN 1476-4598

DOI: 10.1186/s12943-023-01906-8
PMID: 38017545

14 p, 7.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles