Epigenetics Regulation of Lung Cancer: Implications for Clinical Doctor
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Feb 6, 2017
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Abstract
Lung cancer is the leading cause of malingnancy death worldwide. This phenomenon occurs
when detected in the most advanced stages of the
disease (stage III or IV). There are risk factors
described in the generation of this cancer such
us the consumption of tabacco, inhalation and
subsequent accumulation of radon and asbestos
in lung tissue, environmental pollution, the presence of genetic alterations, and the presence of
epigenetic factors regulating the expression or
repression of genes involved in tumor development. Epigenetic regulation mechanisms may
get involved in tumor progression. They are
DNA methylation, histone covalent modification
and the presence of noncoding RNAs. At different stages of tumor progression it described, the
involve of epigenetic mechanisms as regulators
of processes related to proliferation, epithelial
mesenchymal transition, metastasis, apoptosis,
and others describes different stages of the tumor
progression. This review focuses on describing
the role of epigenetics in the progression of the
lung tumor and remarks on the importance of enhancing knowledge in this discipline for diagnosis and treatment
Keywords
epigenetic repression, DNA methylation, histone code, lung neoplasms, chromatin.represión epigenética, metilación de ADN, código de histonas, cáncer de pulmón, cromatina.
References
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H, Ferlay J, Heanue M, Boyle P. Cancer
incidence in five continents. Vol.IX. Lyon: IARC Scientific Publications;
2007.
2. Forman D, Bray F, Brewster DH, Gombe
Mbalawa C, Kohler B, Piñeros M,
Steliarova-Foucher E, Swaminathan R,
Ferlay J, editors. Cancer incidence in
five continents [internet]. Vol. X. Lyon:
Insternational Agency for Research on
Cancer (IARC). Disponible en: http://
ci5.iarc.fr
3. Pardo C, Cendales R. Incidencia, mortalidad
y prevalencia de cáncer en Colombia,
2007-2011. Bogotá: Instituto Nacional de
Cancerología; 2015.
4. Sholl LM. Biomarkers in lung adenocarcinoma:
a decade of progress. Arch
Pathol Lab Med. 2015;139:469-5.
5. Hsieh T, Fischer R. Biology of chromatin
dynamics. Annu Rev Plant Biol.
2005;327-51.
6. Allis D, Caparros M, Jenuwein T, Reinberg
D. Epigenetics. 2nd ed. New York:
Cold Spring Harbor Laboratory Press;
2015.
7. Langevin S, Kratze R, Kelsey K. Epigenetics
of lung cancer. Transl Res.
20015 Jan;165(1):74-90. doi: 10.1016/j.
trsl.2014.03.001
8. Cheng X. Blumenthal R. Coordinated
chromatin control: structural and
functional linkage of DNA and histone
methylation. Biochemistry. 2010 Apr
13;49(14):2999-3008.
9. Liloglou T, Bediaga N, Brown B, Field
J, Davies M. Epigenetic biomarkers
in lung cancer. Cancer Lett. 2012 Jan
28;342(2):200-12.
10. La Salle J, Trasler J. Dynamic expression
of DNMT3a and DNMT3b isoforms during
male germ cell development in the
mouse. Dev Biol. 2006;296:71-8.
11. Rodríguez M, Ascencia N. Metilación
del ADN: un fenómeno epigenético de
importancia médica. Rev Invest Clín.
2004;56(1):56-7.
12. Mehta A, Dobersch S, Romero A, Barreto
G. Epigenetics in lung cancer diagnosis
and therapy. Cancer Metastasis Rev.
2015 Jun;34(2):229-41.
13. Glazer A, Smith M, Ochs M. Integrative
discovery of epigenetically depressed
cancer testis antigens in NSCLC. PLoS
One. 2009;4:e8189.
14. Kim H, Lee C. Expression of cancer-testis
antigens MAGE-A3/6 and NY-ESO-1
in non-small-cell lung carcinomas and
their relationship with immune cell infiltration.
Lung. 2009;187:401-11.
15. Kayser G, Sienel G, Kubitz B. Poor outcome
in primary non-small cell lung cancers
is predicted by transketolase TKTL1
expression. Pathology. 2011;43:719-24.
16. Renaud S, Pugacheva M, Delgado D. Expression
of the CTCF-paralogous cancertestis
gene, brother of the regulator of
imprinted sites (BORIS), is regulated by
three alternative promoters modulated
by CpG methylation and by CTCF and
p53 transcription factors. Nucl Acid Res.
2007;35:7372-88.
17. Hong J, Kang Y, Abdullaev Z. Reciprocal
binding of CTCF and BORIS to the NYESO-
1 promoter coincides with depression
of this cancer-testis gene in lung cancer
cells. Cancer Res. 2005;65:7763-74.
18. Esteller M. Epigenetic gene silencing in
cancer: the DNA hypermethylome. Hum
Mol Genet. 2007 Apr 15;16 Spec No
1:R50-59. doi:10.1093/hmg/ddm018.
19. Rando O, Chang H. Genome wide views
of chromatin structure. Annu Rev Biochem.
2009;78:245-71
20. Kouzarides T. Chromatin modifications
and their function. Cell. 2007;128:693-
705.
21. Zhang Q, Ramlee MK, Brunmeir R, Villanueva
CJ, Halperin D, Xu F. Dynamic
and distinct histone modifications
modulate the expression of key adipogenesis
regulatory genes. Cell Cycle.
2012;11(23):4310.
22. Stojanovicć D, Nikic D, Lazarevic K.
The level of nickel in smoker’s blood
and urine. Cent Eur J Public Health.
2004;12(4):187-9.
23. Sasaki H, Moriyama S, Nakashima Y,
Kobayashi Y, Kiriyama M, Fukai I, Yamakawa
Y, Fujii Y. Histone deacetylase
1 mRNA expression in lung cancer. Lung
Cancer. 2004;46:171-8.
24. Bartling B, Hofmann HS, Boettger T,
Hansen G, Burdach S, Silber RE, Simm
A. Comparative application of antibody
and gene array for expression profiling
in human squamous cell lung carcinoma.
Lung Cancer. 2005;49(2):145-54.
doi:10.1016/j.lungcan.2005.02.006
25. Minamiya Y, Ono T, Saito H, Takahashi
N, Ito M, Motoyama S, Ogawa J. Strong
expression of HDAC3 correlates with
a poor prognosis in patients with adenocarcinoma
of the lung. Tumour Biol.
2010;31(5):533-9. doi: 10.1007/s13277-
010-0066-0.
26. Yanaihara N, Caplen N, Bowman E,
Seike M, Kumamoto K, Yi M, et al.
Unique MicroRNA molecular profiles
in lung cancer diagnosis and prognosis.
Cancer Cell. 2006;9(3):189-98.
27. Yu SL, Chen HY, Chang GC, Chen CY,
Chen HW, Singh S, et al. MicroRNA
signature predicts survival and relapse in
lung. Cancer Cell. 2008;13(1):48-57. doi:
10.1016/j.ccr.2007.12.008
28. Hu Z, Chen X, Zhao Y, Tian T, Jin G,
Shu Y, et al. Serum microRNA signatures
identified in a genome-wide serum
microRNA expression profiling predict
survival of non-small-cell lung cancer
J Clin Oncol. 2010;28(10):1721-6. doi:
10.1200/JCO.2009.24.9342
29. Yuan J, Yue H, Zhang M, Luo J, Liu L,
Wu W, et al. Transcriptional profiling
analysis and functional prediction of long
noncoding RNAs in cancer. Oncotarget.
2016 Jan 23;7(7):8131-42.
30. Lyko F, Brown R. DNA methyltransferase
inhibitors and the development of epigenetic
cancer therapies. J Natl Cancer
Inst. 2005;97(20):1498-506.
31. Komashko V, Farnham P. 5-azacytidina
treatment reorganizes genomic histone
modification patterns. Epigenetics.
2010;5(3):229-40.
32. Jones DR, Moskaluk CH A, Gillenwater
HH, Petroni GR, et al. Phase I Trial of
induction histone deacetylase and proteasome
inhibition followed by surgery
in non-small cell lung cancer. J Thorac
Oncol. 2012 Nov;7(11):1683-90.
33. Prince HM, Bishton MJ, Harrison SJ.
Clinical studies of histone deacetylase
inhibitors. Clin Cancer Res. 2009;
15:3958-69.
34. Glozak MA, Sengupta N, Zhang X, Seto
E. Acetylation and deacetylation of nonhistone
proteins. Gene. 2005;363:15-23.
35. Kim SC, Sprung R, Chen Y, Xu Y, Ball
H, Pei J, et al. Substrate and functional
diversity of lysine acetylation revealed
by aproteomics survey. Mol Cell.
2006;23(4):607-18.
36. Lane AA, Chabner BA. Histone deacetylase
inhibitors in cancer therapy. J Clin
Oncol. 2009;27:5459-68.
37. Langevin S, Kratzke R, Kelsey K. Epigenetics
of lung cancer. Transl Res. 2015
Jan;165(1):74-90.
38. Mayo MW, Denlinger CE, Broad RM,
Yeung F, Reilly ET, Shi Y, et al. Ineffectiveness
of HDAC inhibitors to induce
apoptosis involves the transcriptional
activation of NF-κB through the Akt
pathway. J Biol Chem. 2003;278:
18980-9.
39. McLaughlin KAJ, I Stasik, KM Prise,
PG Johnston, DB Longley. The
HDAC inhibitor vorinostat (SAHA)
down-regulates C-FLIP and sensitizes
human non-small cell lung carcinoma
cell lines to ionising radiation. European
Journal of Cancer. 2012;48(Suppl
5):S272-3. doi:http://dx.doi.org/10.1016/
S0959-8049(12)71732-X
40. Riley JS, Hutchinson R, McArt DG,
Crawford N, Holohan C, Paul I, et al.
Prognostic and therapeutic relevance
of FLIP and procaspase-8 overexpression
in non-small cell lung cancer. Cell
Death Dis. 2013;4:e951. doi: 10.1038/
cddis.2013.481.
41. Gray JE, Haura E, Chiappori A, Tanvetyanon
T, Williams CC, Pinder-Schenck
M, A phase I, pharmacokinetic and pharmacodynamic
study of panobinostat, an
HDAC inhibitor, combinedwith erlotinib
in patients with advanced aerodigestive
tract tumors. Clin Cancer Res. 2014 Mar
15;20(6):1644-55.
42. Greve G, Schiffmann I, Pfeifer D, Pantic
M, Schüler J, Lübbert M. The pan-HDAC
inhibitor panobinostat acts as a sensitizer
for erlotinib activity in EGFR-mutated
and -wildtype non-small cell lung cancer
cells. BMC Cancer. 2015;15:947.
43. Reguart N, Rosell R, Cardenal F, Cardona
AF, Isla D, Palmero R, et al. Phase I/
II trial of vorinostat (SAHA) and erlotinib
for non-small cell lung cancer (NSCLC)
patients with epidermal growth
factor receptor (EGFR) mutations after
erlotinib progression. Lung Cancer. 2014
May;84(2):161-7.
44. Trédaniel R, Descourt D, Moro-Sibilot
J, Misset E, Gachard J, Garcia-Vargas
E, et al. Vorinostat in combination with
gemcitabine and cisplatinum in patients
with advanced non-small cell lung cancer
(NSCLC): A Phase I dose-escalation study.
J Clin Oncol. 2009;27:35-7.
45. Ramalingam SS, Maitland ML, Frankel
P, Argiris AE, Koczywas M, Gitlitz B, et
al. Carboplatin and Paclitaxel in combination
with either vorinostat or placebo
for first-line therapy of advanced nonsmall-
cell lung cancer. J Clin Oncol.
2010;28(1):56-62.
46. Juergens RA, Wrangle J, Vendetti FP,
Murphy SC, Zhao M, Coleman B, et
al. Combination epigenetic therapy
has efficacy in patients with refractory
advanced non-small cell lung cancer.
Cancer Discov. 2011;1(7):598-607. doi:
10.1158/2159-8290.
47. ClinicalTrials.gov. Ph1b/2 Dose-Escalation
Study of Entinostat with Pembrolizumab
in NSCLC with Expansion Cohorts
in NSCLC and Melanoma [internet].
NCT02437136. Disponible en: https://clinicaltrials.
gov/ct2/show/NCT02437136
H, Ferlay J, Heanue M, Boyle P. Cancer
incidence in five continents. Vol.IX. Lyon: IARC Scientific Publications;
2007.
2. Forman D, Bray F, Brewster DH, Gombe
Mbalawa C, Kohler B, Piñeros M,
Steliarova-Foucher E, Swaminathan R,
Ferlay J, editors. Cancer incidence in
five continents [internet]. Vol. X. Lyon:
Insternational Agency for Research on
Cancer (IARC). Disponible en: http://
ci5.iarc.fr
3. Pardo C, Cendales R. Incidencia, mortalidad
y prevalencia de cáncer en Colombia,
2007-2011. Bogotá: Instituto Nacional de
Cancerología; 2015.
4. Sholl LM. Biomarkers in lung adenocarcinoma:
a decade of progress. Arch
Pathol Lab Med. 2015;139:469-5.
5. Hsieh T, Fischer R. Biology of chromatin
dynamics. Annu Rev Plant Biol.
2005;327-51.
6. Allis D, Caparros M, Jenuwein T, Reinberg
D. Epigenetics. 2nd ed. New York:
Cold Spring Harbor Laboratory Press;
2015.
7. Langevin S, Kratze R, Kelsey K. Epigenetics
of lung cancer. Transl Res.
20015 Jan;165(1):74-90. doi: 10.1016/j.
trsl.2014.03.001
8. Cheng X. Blumenthal R. Coordinated
chromatin control: structural and
functional linkage of DNA and histone
methylation. Biochemistry. 2010 Apr
13;49(14):2999-3008.
9. Liloglou T, Bediaga N, Brown B, Field
J, Davies M. Epigenetic biomarkers
in lung cancer. Cancer Lett. 2012 Jan
28;342(2):200-12.
10. La Salle J, Trasler J. Dynamic expression
of DNMT3a and DNMT3b isoforms during
male germ cell development in the
mouse. Dev Biol. 2006;296:71-8.
11. Rodríguez M, Ascencia N. Metilación
del ADN: un fenómeno epigenético de
importancia médica. Rev Invest Clín.
2004;56(1):56-7.
12. Mehta A, Dobersch S, Romero A, Barreto
G. Epigenetics in lung cancer diagnosis
and therapy. Cancer Metastasis Rev.
2015 Jun;34(2):229-41.
13. Glazer A, Smith M, Ochs M. Integrative
discovery of epigenetically depressed
cancer testis antigens in NSCLC. PLoS
One. 2009;4:e8189.
14. Kim H, Lee C. Expression of cancer-testis
antigens MAGE-A3/6 and NY-ESO-1
in non-small-cell lung carcinomas and
their relationship with immune cell infiltration.
Lung. 2009;187:401-11.
15. Kayser G, Sienel G, Kubitz B. Poor outcome
in primary non-small cell lung cancers
is predicted by transketolase TKTL1
expression. Pathology. 2011;43:719-24.
16. Renaud S, Pugacheva M, Delgado D. Expression
of the CTCF-paralogous cancertestis
gene, brother of the regulator of
imprinted sites (BORIS), is regulated by
three alternative promoters modulated
by CpG methylation and by CTCF and
p53 transcription factors. Nucl Acid Res.
2007;35:7372-88.
17. Hong J, Kang Y, Abdullaev Z. Reciprocal
binding of CTCF and BORIS to the NYESO-
1 promoter coincides with depression
of this cancer-testis gene in lung cancer
cells. Cancer Res. 2005;65:7763-74.
18. Esteller M. Epigenetic gene silencing in
cancer: the DNA hypermethylome. Hum
Mol Genet. 2007 Apr 15;16 Spec No
1:R50-59. doi:10.1093/hmg/ddm018.
19. Rando O, Chang H. Genome wide views
of chromatin structure. Annu Rev Biochem.
2009;78:245-71
20. Kouzarides T. Chromatin modifications
and their function. Cell. 2007;128:693-
705.
21. Zhang Q, Ramlee MK, Brunmeir R, Villanueva
CJ, Halperin D, Xu F. Dynamic
and distinct histone modifications
modulate the expression of key adipogenesis
regulatory genes. Cell Cycle.
2012;11(23):4310.
22. Stojanovicć D, Nikic D, Lazarevic K.
The level of nickel in smoker’s blood
and urine. Cent Eur J Public Health.
2004;12(4):187-9.
23. Sasaki H, Moriyama S, Nakashima Y,
Kobayashi Y, Kiriyama M, Fukai I, Yamakawa
Y, Fujii Y. Histone deacetylase
1 mRNA expression in lung cancer. Lung
Cancer. 2004;46:171-8.
24. Bartling B, Hofmann HS, Boettger T,
Hansen G, Burdach S, Silber RE, Simm
A. Comparative application of antibody
and gene array for expression profiling
in human squamous cell lung carcinoma.
Lung Cancer. 2005;49(2):145-54.
doi:10.1016/j.lungcan.2005.02.006
25. Minamiya Y, Ono T, Saito H, Takahashi
N, Ito M, Motoyama S, Ogawa J. Strong
expression of HDAC3 correlates with
a poor prognosis in patients with adenocarcinoma
of the lung. Tumour Biol.
2010;31(5):533-9. doi: 10.1007/s13277-
010-0066-0.
26. Yanaihara N, Caplen N, Bowman E,
Seike M, Kumamoto K, Yi M, et al.
Unique MicroRNA molecular profiles
in lung cancer diagnosis and prognosis.
Cancer Cell. 2006;9(3):189-98.
27. Yu SL, Chen HY, Chang GC, Chen CY,
Chen HW, Singh S, et al. MicroRNA
signature predicts survival and relapse in
lung. Cancer Cell. 2008;13(1):48-57. doi:
10.1016/j.ccr.2007.12.008
28. Hu Z, Chen X, Zhao Y, Tian T, Jin G,
Shu Y, et al. Serum microRNA signatures
identified in a genome-wide serum
microRNA expression profiling predict
survival of non-small-cell lung cancer
J Clin Oncol. 2010;28(10):1721-6. doi:
10.1200/JCO.2009.24.9342
29. Yuan J, Yue H, Zhang M, Luo J, Liu L,
Wu W, et al. Transcriptional profiling
analysis and functional prediction of long
noncoding RNAs in cancer. Oncotarget.
2016 Jan 23;7(7):8131-42.
30. Lyko F, Brown R. DNA methyltransferase
inhibitors and the development of epigenetic
cancer therapies. J Natl Cancer
Inst. 2005;97(20):1498-506.
31. Komashko V, Farnham P. 5-azacytidina
treatment reorganizes genomic histone
modification patterns. Epigenetics.
2010;5(3):229-40.
32. Jones DR, Moskaluk CH A, Gillenwater
HH, Petroni GR, et al. Phase I Trial of
induction histone deacetylase and proteasome
inhibition followed by surgery
in non-small cell lung cancer. J Thorac
Oncol. 2012 Nov;7(11):1683-90.
33. Prince HM, Bishton MJ, Harrison SJ.
Clinical studies of histone deacetylase
inhibitors. Clin Cancer Res. 2009;
15:3958-69.
34. Glozak MA, Sengupta N, Zhang X, Seto
E. Acetylation and deacetylation of nonhistone
proteins. Gene. 2005;363:15-23.
35. Kim SC, Sprung R, Chen Y, Xu Y, Ball
H, Pei J, et al. Substrate and functional
diversity of lysine acetylation revealed
by aproteomics survey. Mol Cell.
2006;23(4):607-18.
36. Lane AA, Chabner BA. Histone deacetylase
inhibitors in cancer therapy. J Clin
Oncol. 2009;27:5459-68.
37. Langevin S, Kratzke R, Kelsey K. Epigenetics
of lung cancer. Transl Res. 2015
Jan;165(1):74-90.
38. Mayo MW, Denlinger CE, Broad RM,
Yeung F, Reilly ET, Shi Y, et al. Ineffectiveness
of HDAC inhibitors to induce
apoptosis involves the transcriptional
activation of NF-κB through the Akt
pathway. J Biol Chem. 2003;278:
18980-9.
39. McLaughlin KAJ, I Stasik, KM Prise,
PG Johnston, DB Longley. The
HDAC inhibitor vorinostat (SAHA)
down-regulates C-FLIP and sensitizes
human non-small cell lung carcinoma
cell lines to ionising radiation. European
Journal of Cancer. 2012;48(Suppl
5):S272-3. doi:http://dx.doi.org/10.1016/
S0959-8049(12)71732-X
40. Riley JS, Hutchinson R, McArt DG,
Crawford N, Holohan C, Paul I, et al.
Prognostic and therapeutic relevance
of FLIP and procaspase-8 overexpression
in non-small cell lung cancer. Cell
Death Dis. 2013;4:e951. doi: 10.1038/
cddis.2013.481.
41. Gray JE, Haura E, Chiappori A, Tanvetyanon
T, Williams CC, Pinder-Schenck
M, A phase I, pharmacokinetic and pharmacodynamic
study of panobinostat, an
HDAC inhibitor, combinedwith erlotinib
in patients with advanced aerodigestive
tract tumors. Clin Cancer Res. 2014 Mar
15;20(6):1644-55.
42. Greve G, Schiffmann I, Pfeifer D, Pantic
M, Schüler J, Lübbert M. The pan-HDAC
inhibitor panobinostat acts as a sensitizer
for erlotinib activity in EGFR-mutated
and -wildtype non-small cell lung cancer
cells. BMC Cancer. 2015;15:947.
43. Reguart N, Rosell R, Cardenal F, Cardona
AF, Isla D, Palmero R, et al. Phase I/
II trial of vorinostat (SAHA) and erlotinib
for non-small cell lung cancer (NSCLC)
patients with epidermal growth
factor receptor (EGFR) mutations after
erlotinib progression. Lung Cancer. 2014
May;84(2):161-7.
44. Trédaniel R, Descourt D, Moro-Sibilot
J, Misset E, Gachard J, Garcia-Vargas
E, et al. Vorinostat in combination with
gemcitabine and cisplatinum in patients
with advanced non-small cell lung cancer
(NSCLC): A Phase I dose-escalation study.
J Clin Oncol. 2009;27:35-7.
45. Ramalingam SS, Maitland ML, Frankel
P, Argiris AE, Koczywas M, Gitlitz B, et
al. Carboplatin and Paclitaxel in combination
with either vorinostat or placebo
for first-line therapy of advanced nonsmall-
cell lung cancer. J Clin Oncol.
2010;28(1):56-62.
46. Juergens RA, Wrangle J, Vendetti FP,
Murphy SC, Zhao M, Coleman B, et
al. Combination epigenetic therapy
has efficacy in patients with refractory
advanced non-small cell lung cancer.
Cancer Discov. 2011;1(7):598-607. doi:
10.1158/2159-8290.
47. ClinicalTrials.gov. Ph1b/2 Dose-Escalation
Study of Entinostat with Pembrolizumab
in NSCLC with Expansion Cohorts
in NSCLC and Melanoma [internet].
NCT02437136. Disponible en: https://clinicaltrials.
gov/ct2/show/NCT02437136
How to Cite
Rojas Moreno, A. P., Bruges, R. E., Cañas Arboleda, A., & Jaramillo García, L. F. (2017). Epigenetics Regulation of Lung Cancer: Implications for Clinical Doctor. Universitas Medica, 57(3), 332–347. https://doi.org/10.11144/Javeriana.umed57-3.recp
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