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DNA and histone modifications as potent diagnostic and therapeutic targets to advance non-small cell lung cancer management from the perspective of 3P medicine

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Abstract

Lung cancer has a very high mortality in females and males. Most (~ 85%) of lung cancers are non-small cell lung cancers (NSCLC). When lung cancer is diagnosed, most of them have either local or distant metastasis, with a poor prognosis. In order to achieve better outcomes, it is imperative to identify the molecular signature based on genetic and epigenetic variations for different NSCLC subgroups. We hypothesize that DNA and histone modifications play significant roles in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Epigenetics has a significant impact on tumorigenicity, tumor heterogeneity, and tumor resistance to chemotherapy, targeted therapy, and immunotherapy. An increasing interest is that epigenomic regulation is recognized as a potential treatment option for NSCLC. Most attention has been paid to the epigenetic alteration patterns of DNA and histones. This article aims to review the roles DNA and histone modifications play in tumorigenesis, early detection and diagnosis, and advancements and therapies of NSCLC, and also explore the connection between DNA and histone modifications and PPPM, which may provide an important contribution to improve the prognosis of NSCLC. We found that the success of targeting DNA and histone modifications is limited in the clinic, and how to combine the therapies to improve patient outcomes is necessary in further studies, especially for predictive diagnostics, targeted prevention, and personalization of medical services in the 3P medicine approach. It is concluded that DNA and histone modifications are potent diagnostic and therapeutic targets to advance non-small cell lung cancer management from the perspective of 3P medicine.

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Data availability

All data and materials are available in the current manuscript.

Abbreviations

APC:

Adenomatous polyposis coli

ALK:

Anaplastic lymphoma kinase

CASP1:

Silenced caspase 1

CNVs:

Copy number variations

DSBs:

Double-strand breaks

DNMTs:

DNA methyltransferases

DNAm:

DNA methylation

ELMO3:

Engulfment and cell motility 3

EGFR:

Epidermal growth factor receptor

FHIT:

Fragile histidine triad

HR:

Homologous recombination

hMLH1:

Human mutL homolog 1

HRM:

Methylation-specific high-resolution melting

HDACis:

Histone deacetylase inhibitors

HATs:

Acetyltransferases

KLF2:

Kruppel-like factor 2

LUAD:

Lung adenocarcinoma

LOH:

Loss of heterozygosity

m6A:

N6-methyladenosine

MMP:

Matrix metalloproteinase

NSCLC:

Non-small cell lung cancer

NHEJ:

Non-homologous end joining

OG:

8-Oxo-7,8-dihydroguanine

OS:

Overall survival

PT:

Phosphorothioate

PD-1:

Anti-programmed cell death protein 1

PD-L1:

Anti-programmed cell death ligand 1

PTMs:

Posttranslational modifications

PFS:

Progression-free survival

ROS:

Reactive oxygen species

RARbeta:

Retinoic acid receptor-beta

SMYD2:

SET and MYND domain-containing 2

SCLC:

Small cell lung cancer

TMB:

Tumor mutation burden

TCGA:

The Cancer Genome Atlas

TKIs:

Tyrosine kinase inhibitors

TF:

Transcription factor

TET:

Ten-eleven translocation enzymes

TSGs:

Tumor suppressor genes

5mC:

5-Methylcytosine

5hmU:

5-Hydroxymethyluracil

5fU:

5-Formyluracil

5hmU:

5-Hydroxymethyluracil

5fU:

5-Formyluracil

5-Aza-dC:

5-Aza-2′-deoxycytidine

5-aza-CdR:

5-Aza-2′-deoxycytidine

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Acknowledgements

The authors acknowledge the financial support from the Shandong First Medical University Talent Introduction Funds (to X.Z.), Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR202103020356/ZR2021MH156 to X.Z.), Taishan Scholar Engineering Project Special Funds (to X.Z.), and the Academic Promotion Program of Shandong First Medical University (2019ZL002).

Funding

This work was supported by the Shandong First Medical University Talent Introduction Funds (to X.Z.), Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR202103020356/ZR2021MH156 to X.Z.), Taishan Scholar Engineering Project Special Funds (to X.Z.), and the Academic Promotion Program of Shandong First Medical University (2019ZL002).

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  1. Guodong Zhang and Zhengdan Wang contributed equally to this work.

Authors and Affiliations

  1. Thoracic Surgery Department, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Shandong, 250117, Jinan, People’s Republic of China

    Guodong Zhang, Zhengdan Wang, Pingping Song & Xianquan Zhan

  2. Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong, 250117, People’s Republic of China

    Guodong Zhang, Zhengdan Wang, Pingping Song & Xianquan Zhan

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  1. Guodong Zhang
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G.Z. and Z.W. collected and analyzed literature, wrote the manuscript, they contributed equally to the manuscript. P.S. participated in collection and analysis of literature. X.Z. conceived the concept, designed the manuscript, coordinated, and critically revised the manuscript, and was responsible for the corresponding works. All authors approved the final manuscript.

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Correspondence to Xianquan Zhan.

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Zhang, G., Wang, Z., Song, P. et al. DNA and histone modifications as potent diagnostic and therapeutic targets to advance non-small cell lung cancer management from the perspective of 3P medicine. EPMA Journal 13, 649–669 (2022). https://doi.org/10.1007/s13167-022-00300-6

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