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KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches
Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581295/ https://www.ncbi.nlm.nih.gov/pubmed/34778065 http://dx.doi.org/10.3389/fonc.2021.750315 |
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author | Varghese, Benluvankar Del Gaudio, Nunzio Cobellis, Gilda Altucci, Lucia Nebbioso, Angela |
author_facet | Varghese, Benluvankar Del Gaudio, Nunzio Cobellis, Gilda Altucci, Lucia Nebbioso, Angela |
author_sort | Varghese, Benluvankar |
collection | PubMed |
description | Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in deregulating gene expression, leading to uncontrolled cell proliferation and cancer progression. Aberrant histone modifications are one of the most frequent epigenetic mechanisms occurring in cancer. In particular, methylation and demethylation of specific lysine residues alter gene accessibility via histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The KDM family includes more than 30 members, grouped into six subfamilies and two classes based on their sequency homology and catalytic mechanisms, respectively. Specifically, the KDM4 gene family comprises six members, KDM4A-F, which are associated with oncogene activation, tumor suppressor silencing, alteration of hormone receptor downstream signaling, and chromosomal instability. Blocking the activity of KDM4 enzymes renders them “druggable” targets with therapeutic effects. Several KDM4 inhibitors have already been identified as anticancer drugs in vitro in BC cells. However, no KDM4 inhibitors have as yet entered clinical trials due to a number of issues, including structural similarities between KDM4 members and conservation of the active domain, which makes the discovery of selective inhibitors challenging. Here, we summarize our current knowledge of the molecular functions of KDM4 members in BC, describe currently available KDM4 inhibitors, and discuss their potential use in BC therapy. |
format | Online Article Text |
id | pubmed-8581295 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85812952021-11-12 KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches Varghese, Benluvankar Del Gaudio, Nunzio Cobellis, Gilda Altucci, Lucia Nebbioso, Angela Front Oncol Oncology Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in deregulating gene expression, leading to uncontrolled cell proliferation and cancer progression. Aberrant histone modifications are one of the most frequent epigenetic mechanisms occurring in cancer. In particular, methylation and demethylation of specific lysine residues alter gene accessibility via histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The KDM family includes more than 30 members, grouped into six subfamilies and two classes based on their sequency homology and catalytic mechanisms, respectively. Specifically, the KDM4 gene family comprises six members, KDM4A-F, which are associated with oncogene activation, tumor suppressor silencing, alteration of hormone receptor downstream signaling, and chromosomal instability. Blocking the activity of KDM4 enzymes renders them “druggable” targets with therapeutic effects. Several KDM4 inhibitors have already been identified as anticancer drugs in vitro in BC cells. However, no KDM4 inhibitors have as yet entered clinical trials due to a number of issues, including structural similarities between KDM4 members and conservation of the active domain, which makes the discovery of selective inhibitors challenging. Here, we summarize our current knowledge of the molecular functions of KDM4 members in BC, describe currently available KDM4 inhibitors, and discuss their potential use in BC therapy. Frontiers Media S.A. 2021-10-28 /pmc/articles/PMC8581295/ /pubmed/34778065 http://dx.doi.org/10.3389/fonc.2021.750315 Text en Copyright © 2021 Varghese, Del Gaudio, Cobellis, Altucci and Nebbioso https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Varghese, Benluvankar Del Gaudio, Nunzio Cobellis, Gilda Altucci, Lucia Nebbioso, Angela KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title | KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title_full | KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title_fullStr | KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title_full_unstemmed | KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title_short | KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches |
title_sort | kdm4 involvement in breast cancer and possible therapeutic approaches |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581295/ https://www.ncbi.nlm.nih.gov/pubmed/34778065 http://dx.doi.org/10.3389/fonc.2021.750315 |
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