Epigenetic control of gene expression: Potential implications for cancer treatment

https://doi.org/10.1016/j.critrevonc.2017.01.020Get rights and content

Highlights

  • The present manuscript describes the impact of epigenetic changes in cancer development, highlighting the crucial role of them mainly in some phases of the carcinogenesis.

  • Epigenetic changes do not regard DNA sequence, but they strong influence the expression of tumor suppressor genes and oncogenes, altering their balance and thus favoring carcinogenesis.

  • Several drugs targeting the so called ‘epigenetic code’ have been tested in clinical trials and some of them have yet been approved for use in the clinical practice.

  • Nevertheless, the role of epigenetic drugs in the treatment of solid tumors is not as clear as with the other hand it is in those haematological., and in this review we will try to explain the reasons.

Abstract

Epigenetic changes are defined as inherited modifications that are not present in DNA sequence. Gene expression is regulated at various levels and not only in response to DNA modifications. Examples of epigenetic control are DNA methylation, histone deacetylation and mi-RNA expression. Methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. Similarly, histone deacetylation can lead to oncogene activation. mi-RNA are small (18–20 nucleotides) non-coding RNA fragments capable of inhibiting other m-RNA, ultimately altering the balance in oncogene and tumor suppressor gene expression. It has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. As matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. Recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors work alone or in combination with other therapeutic agents. To date, a number of epigenetic inhibitors have been approved for cancer treatment. The main challenge in the field of epigenetic inhibitors is their lack of specificity. In this review article we describe their mechanisms of action and potential in cancer treatment.

Section snippets

Background

Epigenetics means “beyond genetic” or “other than genetic” and is defined as a group of inheritable changes in gene expression occurring without alterations in DNA sequence. In the eukaryotic nucleus, DNA is compacted in a structure defined as chromatin, whose basic unit is the nucleosome. Each nucleosome is formed by a multiproteic complex named “histone”, surrounded by about 145–147 pairs of DNA bases. Histone is an octamer constituted by four pairs of proteins, called H3, H4, H2A and H2B.

Epigenetics and cancer

Cancer is the result of DNA aberrations causing deregulation of cell cycle, apoptosis and cell survival. DNA mutations involving oncogenes (OG) the genes able to promote cell survival and tumor suppressor genes (TSG) are well known to be responsible for cancer initiation, promotion and progression. Nevertheless, recent data have suggested a crucial role for epigenetic mechanisms in cancer development. Indeed, carcinogenesis, cannot be explained only by genetic alterations, but also involve

Drugs targeting the epigenetic code

Epigenetic changes are often found in both solid and hematological malignancies. Interestingly, epigenetic changes are reversible modifications. This feature makes them an attractive target for cancer therapy. Defining and restoring the normal and pre-existent epigenetic landscape has became the focus of active investigation and several “epigenetic drugs” have been tested in the clinical setting. An effective anticancer treatment requires the identification of the target and the demonstration

Conclusions

Cancer has a very complex pathogenesis and pathophysiology and its development requires the accumulation of multiple genomic aberrations. These changes can involve OGs, causing their hyper-activation, or TSGs, inducing their silencing, but the final result is cell-cycle deregulation and apoptosis inhibition. DNA mutations alone are probably important for “iniziation” of carcinogenesis. The following step of carcinogenesis is named “promotion”, namely the accumulation of other DNA changes which

Author contributions

Dr Perri and Dr. Della Vittoria Scarpati designed the work. All the authors collected the data. Dr Perri wrote the paper and Dr Giuliano edited the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

References (74)

  • D.B. Seligson et al.

    Global levels of histone modifications predict prognosis in different cancers

    Am. J. Pathol.

    (2009)
  • M. Argos et al.

    Gene-specific differential DNA methylation and chronic arsenic exposure in an epigenome-wide association study of adults in Bangladesh

    Environ. Health Perspect.

    (2015)
  • K.M. Bernt et al.

    Targeting epigenetic programs in MLL-rearranged leukemias

    Hematol. Am. Soc. Hematol. Educ. Progr.

    (2011)
  • C.J. Braun et al.

    Rewiring the solid tumor epigenome for cancer therapy

    Expert Rev. Anticancer Ther.

    (2016)
  • J.M. Brown et al.

    The unique physiology of solid tumors: opportunities (and problems) for cancer therapy

    Cancer Res.

    (1998)
  • A.T. Brunetto et al.

    A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors

    J. Clin. Oncol.

    (2009)
  • Q.W. Chen et al.

    Epigenetic regulation and cancer (review)

    Oncol. Rep.

    (2014)
  • D.A. Chistiakov et al.

    Epigenetically active drugs inhibiting DNA methylation and histone deacetylation

    Curr. Pharm. Des.

    (2016, October)
  • Y. Cohen et al.

    The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix

    Clin. Cancer Res.

    (2003)
  • G. Della Vittoria Scarpati et al.

    Analysis of differential miRNA expression in primary tumor and stroma of colorectal cancer patients

    Biomed. Res. Int.

    (2014)
  • P.H. Domer et al.

    Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product

    Proc. Natl. Acad. Sci. U. S. A.

    (1993)
  • M.A. Elliott et al.

    Therapy-related acute promyelocytic leukemia (t-APL): observations on APL pathogenesis

    J. Clin. Oncol.

    (2011)
  • M. Esteller

    Epigenetics in cancer

    N. Engl. J. Med.

    (2008)
  • M. Esteller et al.

    Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma

    J. Natl. Cancer Inst.

    (2002)
  • D. Gao et al.

    The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer

    Oncotarget

    (2016)
  • K. Gołąbek et al.

    Potential use of histone deacetylase inhibitors in cancer therapy

    Contemp. Oncol. (Pozn.)

    (2015)
  • S.M. Gollin

    Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: a next generation window to the biology of disease

    Genes Chromosomes Cancer

    (2014)
  • R. Hamamoto et al.

    Dysregulation of protein methyltransferases in human cancer: an emerging target class for anticancer therapy

    Cancer Sci.

    (2016)
  • R. Hamamoto et al.

    Enhanced SMYD3 expression is essential for the growth of breast cancer cells

    Cancer Sci.

    (2006)
  • S.M. Horwitz et al.

    Complete responses (CR/CRu) on a phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL)

    J. Clin. Oncol.

    (2011)
  • Y.Q. Huang et al.

    Association between RASSF1A promoter methylation and renal cell cancer susceptibility: a meta-analysis

    Genet. Mol. Res.

    (2016)
  • B. Jones et al.

    The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure

    PLoS Genet.

    (2008)
  • E. Kaminskas et al.

    FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension

    Oncologist

    (2005)
  • H.M. Kantarjian et al.

    Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience

    Cancer

    (2007)
  • S. Kristiansen et al.

    Detection and monitoring of hypermethylated RASSF1A in serum from patients with metastatic breast cancer

    Clin. Epigenet.

    (2016)
  • S.K. Kurdistani

    Histone modifications in cancer biology and prognosis

    Prog. Drug Res.

    (2011)
  • M.N. Lee et al.

    Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer

    Clin. Cancer Res.

    (2007)
  • Cited by (117)

    View all citing articles on Scopus
    View full text