Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets

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.

MicroRNA-21 Expression as a Prognostic Biomarker in Oral Cancer: Systematic Review and Meta-Analysis

“…The main genetic alterations affecting carcinogenesis involve changes in tumor suppressors (APC, p53 BRCA2, PTCH, NF1, VHL, Rb BCL2, SWI/SNF, p16, CD95, ST5, YPEL3, ST7, and ST14) and oncogenes (Ras, jun, fas, erbA, abl, raf, gsp, sis, erbB, and fms) in addition the onset and progression of oral cancer involve changes of DNA methylation, histone modifications, and non-coding alterations of RNA, including microRNAs (miRNA) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer

“…It was found that HDACs overexpress in several cancers and appeared to have potential as therapeutic targets ( 18 ). HDAC overexpression can lead to TSG silencing or altered transcription by influencing genes encoding HAT enzymes or binding elements of HAT and HDAC enzymes, which are associated with carcinogenesis ( 13 ). Similarly, histone methyltransferases (HMTs) and histone demethylases (KDMs) regulate the histone methylation dynamically ( 74 ).…”

“…Several epigenetic therapies for NSCLC were carried out in clinical trials ( Table 1 ). Detecting the molecular characteristics of NSCLC subtypes, such as genetics and epigenetic variation, was critical for choosing the proper therapy for combination ( 13 ) while chemotherapy resistance was also found to be associated with epigenetic changes ( 188 ). Besides, DNA methylation is a double-sided procedure, unlike the changes of genetic information involving gene mutations or deletions.…”

“…The methylation patterns can offer conditions with molecular causes underlying the clinical advantage for immune checkpoint blockade (ICB) therapy ( 10 , 11 ). Despite that first-line single agent ICB exhibited restricted activity in EGFR mutated NSCLC, the combination of immunotherapy and targeted agents has gained wide attention in both EGFR and ALK-positive NSCLC patients ( 12 ) Simultaneously, epigenetic marks led to the detection of potential cancer biomarkers for early screening, monitoring, and therapeutic methods of NSCLC ( 13 ).…”

Establishment and characterization of a novel highly malignant lung cancer cell line ZX2021H derived from a metastatic lymph node lesion

“…Lung cancer is a highly malignant tumor with the inherent biological properties of rapid proliferation and early spread, leading to a poor prognosis. Lung cancer is generally classified into two main histological types: small cell lung cancer and non‐small cell lung cancer (NSCLC), of which NSCLC accounts for approximately 85% of all cases 1–4 . Despite substantial progress in the treatment of NSCLC, including the advent of immunotherapy and various targeted therapies, the prognosis of patients with NSCLC remains poor and the 5‐year overall survival rate is still <19% 5–7 .…”