Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, s...

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Autores principales:	Khuloud Bajbouj, Abeer Al-Ali, Rakhee K. Ramakrishnan, Maha Saber-Ayad, Qutayba Hamid
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	histone deacetylase demethylase methyltransferase KDM LSD tumour suppressor genes Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/3cb0adb3823548a79aea316663e8384b
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spelling	oai:doaj.org-article:3cb0adb3823548a79aea316663e8384b2021-11-11T17:09:41ZHistone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets10.3390/ijms2221117011422-00671661-6596https://doaj.org/article/3cb0adb3823548a79aea316663e8384b2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11701https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.Khuloud BajboujAbeer Al-AliRakhee K. RamakrishnanMaha Saber-AyadQutayba HamidMDPI AGarticlehistone deacetylasedemethylasemethyltransferaseKDMLSDtumour suppressor genesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11701, p 11701 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	histone deacetylase demethylase methyltransferase KDM LSD tumour suppressor genes Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	histone deacetylase demethylase methyltransferase KDM LSD tumour suppressor genes Biology (General) QH301-705.5 Chemistry QD1-999 Khuloud Bajbouj Abeer Al-Ali Rakhee K. Ramakrishnan Maha Saber-Ayad Qutayba Hamid Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
description	Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.
format	article
author	Khuloud Bajbouj Abeer Al-Ali Rakhee K. Ramakrishnan Maha Saber-Ayad Qutayba Hamid
author_facet	Khuloud Bajbouj Abeer Al-Ali Rakhee K. Ramakrishnan Maha Saber-Ayad Qutayba Hamid
author_sort	Khuloud Bajbouj
title	Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
title_short	Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
title_full	Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
title_fullStr	Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
title_full_unstemmed	Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
title_sort	histone modification in nsclc: molecular mechanisms and therapeutic targets
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3cb0adb3823548a79aea316663e8384b
work_keys_str_mv	AT khuloudbajbouj histonemodificationinnsclcmolecularmechanismsandtherapeutictargets AT abeeralali histonemodificationinnsclcmolecularmechanismsandtherapeutictargets AT rakheekramakrishnan histonemodificationinnsclcmolecularmechanismsandtherapeutictargets AT mahasaberayad histonemodificationinnsclcmolecularmechanismsandtherapeutictargets AT qutaybahamid histonemodificationinnsclcmolecularmechanismsandtherapeutictargets
_version_	1718432171281088512

Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

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