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Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets - PubMed

  • ️Fri Jan 01 2021

Review

Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

Khuloud Bajbouj et al. Int J Mol Sci. 2021.

Abstract

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.

Keywords: KDM; LSD; demethylase; histone deacetylase; methyltransferase; tumour suppressor genes; vorinostat.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Epigenetic regulatory mechanisms linked to lung cancer. (A) Acetylation of histones reduces its positive charge, thereby relaxing the tightly coiled negatively charged DNA wrapped around them. The open chromatin structure enables access to the transcriptional machinery (including RNA polymerase and transcriptional factors), resulting in active gene transcription. Conversely, methylation of histones is generally associated with a condensed chromatin structure, which prevents access to the transcriptional machinery repressing gene transcription. While histone acetyltransferases (HATs) introduce acetyl groups onto lysine residues on histones, histone deacetylases (HDACs) carry out deacetylation of histones. Similarly, histone methyltransferases (HMTs) promote the addition of mono-, di-, or tri-methyl groups at arginine and/or lysine residues on histones, while histone demethylases (HDMs) are responsible for removing these methyl groups. (B) Cancer cells display hypermethylation of multiple promoter CpG islands as well as a genome-wide loss of DNA methylation at sporadic CpGs. Methyl-binding proteins are further capable of recruiting HDACs. The overexpression of HMTs and HDACs thus results in reduced chromatin access and silencing of TSG. This abnormal epigenetic activity paves the way to lung cancer development and progression.

Figure 2
Figure 2

Histone methylation landscape in lung cancer. The lysines K4, K9, K27, K36, and K79 on histone H3 and K20 of histone H4 are amenable for modification by methylation. While H3K4 and H3K36 methylation activate gene transcription, H3K9, H3K27, H3K79, and H4K20 methylation suppress gene transcription. Histone lysine methyltransferases (KMTs) add methyl groups to histones and are ‘writers’ of the histone code. SMYD3 targets H3K36, and EZH2 mediates trivalent methylation of H3K27, causing chromatin condensation and subsequent repression of TSG transcription. On the other hand, demethylases, such as KDMs, are known as ‘erasers’ of methyl groups, and consequently, KDM1A/LSD1 targets H3K4me2/me1 and H3K9me2/me1.

Figure 3
Figure 3

Chemical Structure of Vorinostat [92].

Figure 4
Figure 4

Multiple mechanisms of action of vorinostat in NSCLC.

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