Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

• Published in: International journal of molecular sciences 2021-10, Vol.22 (21), p.11701
• Main Authors: Bajbouj, Khuloud, Al-Ali, Abeer, Ramakrishnan, Rakhee K, Saber-Ayad, Maha, Hamid, Qutayba
• Format: Article
• Language: English
• Subjects: Acetylation; Adenocarcinoma; Animals; Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - therapy; Cell cycle; Clinical trials; Deacetylation; demethylase; DNA methylation; Drug resistance; Enzymes; Epigenesis, Genetic; Epigenetics; Gene expression; Genetic diversity; Growth factors; Heterogeneity; Histone Code; Histone deacetylase; Histones; Histones - metabolism; Humans; Immunotherapy; KDM; LSD; Lung cancer; Lung carcinoma; Metastases; Methylation; methyltransferase; MicroRNAs; Molecular modelling; Molecular Targeted Therapy; Mutation; Non-small cell lung carcinoma; Pattern recognition; Phosphorylation; Pollutants; Proteins; Review; Smoking; Squamous cell carcinoma; Therapeutic applications; Therapeutic targets; Transcription; Transcription factors; Tumors; tumour suppressor genes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222111701

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.