ArticleThe Journal of clinical investigation2018
Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 51 citations in OpenAlex.
- Epigenetic editing: from concept to clinic.Nature reviews. Drug discovery · 2026Review
- Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation.Cancer research · 2025Article
- Targeting kinases that regulate programmed cell death: a new therapeutic strategy for breast cancer.Journal of translational medicine · 2025Review
- Review
- The Tumor Suppressor Par-4 Regulates Adipogenesis by Transcriptional Repression of PPARγ.Cells · 2024Article
- Pharmacological targeting of the cancer epigenome.Nature cancer · 2024Review
- Anticancer genes (NOXA, PAR-4, TRAIL) are de-regulated in breast cancer patients and can be targeted by using a ribosomal inactivating plant protein (riproximin).Molecular biology reports · 2023Article
- Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis.Signal transduction and targeted therapy · 2022Review
- Epigenetic Editing in Prostate Cancer: Challenges and Opportunities.Epigenetics · 2022Review
- UACA locus is associated with breast cancer chemoresistance and survival.NPJ breast cancer · 2022Article
- APOBEC Mutagenesis Inhibits Breast Cancer Growth through Induction of T cell-Mediated Antitumor Immune Responses.Cancer immunology research · 2022Article
- Combined Evaluation of MAP1LC3B and SQSTM1 for Biological and Clinical Significance in Ductal Carcinoma of Breast Cancer.Biomedicines · 2021Article
- miR-217-5p Inhibits Invasion and Metastasis of Prostate Cancer by Targeting Clusterin.Mammalian genome : official journal of the International Mammalian Genome Society · 2021Article
- Clinical Significance and the Role of Guanylate-Binding Protein 5 in Oral Squamous Cell Carcinoma.Cancers · 2021Article
- Context-dependent effects of whole-genome duplication during mammary tumor recurrence.Scientific reports · 2021Article
- Fabrication of methotrexate-loaded gold nanoconjugates and its enhanced anticancer activity in breast cancer.3 Biotech · 2021Article
- DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway.Oncogene · 2021Article
- Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy.NPJ breast cancer · 2021Article
- Identification of Key Transcription Factors and Immune Infiltration Patterns Associated With Breast Cancer Prognosis Using WGCNA and Cox Regression Analysis.Frontiers in oncology · 2021Article
- G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program.Cell reports · 2020Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Tumor relapse is the leading cause of death in breast cancer, largely due to the fact that recurrent tumors are frequently resistant to chemotherapy. We previously reported that downregulation of the proapoptotic protein Par-4 promotes tumor recurrence in genetically engineered mouse models of breast cancer recurrence. In the present study, we examined the mechanism and functional significance of Par-4 downregulation in recurrent tumors. We found that epithelial-to-mesenchymal transition (EMT) promotes epigenetic silencing of Par-4 in recurrent tumors. Par-4 silencing proceeded through binding of the EMT transcription factor Twist to the Par-4 promoter, where Twist induced a unique bivalent chromatin domain. This bivalent configuration conferred plasticity at the Par-4 promoter, and Par-4 silencing could be reversed with pharmacologic inhibitors of Ezh2 and HDAC1/2. Using an epigenome editing approach to reexpress Par-4 by specifically reversing the histone modifications found in recurrent tumors, we found that Par-4 reexpression sensitized recurrent tumors to chemotherapy in vitro and in vivo. Upon reexpression, Par-4 bound to the protein phosphatase PP1, caused widespread changes in phosphorylation of cytoskeletal proteins, and cooperated with microtubule-targeting drugs to induce mitotic defects. These results identify Twist-induced epigenetic silencing of Par-4 as a targetable axis that promotes chemoresistance in recurrent breast cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.