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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.750315/full |
| _version_ | 1819032387745480704 |
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| author | Benluvankar Varghese Nunzio Del Gaudio Gilda Cobellis Lucia Altucci Lucia Altucci Angela Nebbioso Angela Nebbioso |
| author_facet | Benluvankar Varghese Nunzio Del Gaudio Gilda Cobellis Lucia Altucci Lucia Altucci Angela Nebbioso Angela Nebbioso |
| author_sort | Benluvankar Varghese |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T07:01:08Z |
| format | Article |
| id | doaj.art-b97fca655c0f4f52a6ba5583fbd1b552 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T07:01:08Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b97fca655c0f4f52a6ba5583fbd1b5522022-12-21T19:12:13ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.750315750315KDM4 Involvement in Breast Cancer and Possible Therapeutic ApproachesBenluvankar Varghese0Nunzio Del Gaudio1Gilda Cobellis2Lucia Altucci3Lucia Altucci4Angela Nebbioso5Angela Nebbioso6Department of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, ItalyDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, ItalyDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, ItalyDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, ItalyBiogem Institute of Molecular Biology and Genetics, Ariano Irpino, ItalyDepartment of Precision Medicine, University of Campania Luigi Vanvitelli, Napoli, ItalySaint Camillus International University of Health and Medical Sciences, Rome, ItalyBreast 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.750315/fullepigeneticshistone demethylationKDM4 inhibitorsJMJD2KDM4 |
| spellingShingle | Benluvankar Varghese Nunzio Del Gaudio Gilda Cobellis Lucia Altucci Lucia Altucci Angela Nebbioso Angela Nebbioso KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches Frontiers in Oncology epigenetics histone demethylation KDM4 inhibitors JMJD2 KDM4 |
| 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 | epigenetics histone demethylation KDM4 inhibitors JMJD2 KDM4 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.750315/full |
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