Epigenetic modifications in poorly differentiated and anaplastic thyroid cancer

doi:10.1016/j.mce.2017.05.022

Molecular and Cellular Endocrinology

Volume 469, 5 July 2018, Pages 23-37

https://doi.org/10.1016/j.mce.2017.05.022 Get rights and content

Highlights

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Epigenetic alterations may play potentially decisive roles in the origin and the aggressive clinical course of PDTC and ATC.
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Epigenetic deregulations in PDTC and ATC include DNA methylation, histone and chromatin modification, and ncRNA aberration.
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Understanding the mechanism of PDTC and ATC epigenetic alterations may lead to the design of novel therapeutic strategies.

Abstract

Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex. A deeper understanding of the signaling pathways affected by epigenetic dysregulation may improve prognostic testing and support the advancement of thyroid-specific epigenetic therapies. This review outlines the current understanding of epigenetic alterations observed in PDTC and ATC and explores the potential for exploiting this understanding in developing novel therapeutic strategies.

Introduction

Thyroid cancer is the most common endocrine malignancy and has had a consistently increasing incidence for the past four decades (Horn-Ross et al., 2014, La Vecchia et al., 2015, Kitahara and Sosa, 2016). The vast majority (>95%) of thyroid cancers are derived from follicular epithelial cells while the remainder arises from parafollicular cells (Kitahara and Sosa, 2016). Follicular cell-based thyroid cancer is divided into three major categories: well-differentiated thyroid carcinoma (WDTC), poorly differentiated thyroid carcinoma (PDTC), and undifferentiated or anaplastic thyroid carcinoma (ATC). WDTC includes follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). Among the major thyroid cancer types, ATC is the most rare and aggressive variant (Glaser et al., 2016). Because of its high proliferative index and invasive behavior, the disease-specific mortality of ATC is 69.4% at 6 months and 80.7% at 12 months (Kebebew et al., 2005). The dismal prognosis of ATC is partially due to its inherent resistance to both radioactive iodine and conventional chemotherapy. As the tumor cells of PDTC and ATC lack appreciable expression of the sodium-iodide symporter (NIS), they are incapable of iodine uptake (Spitzweg et al., 2001, O'Neill and Shaha, 2013, Setia and Barletta, 2014). Moreover, ATC cells may not secrete thyroglobulin and are potentially refractory to thyroid stimulating hormone (TSH) because of thyrotropin receptor deficiency on their plasma cell membrane. The combination of these tumor characteristics significantly limits the efficacy of conventional radioactive iodine therapy (Spitzweg et al., 2001, O'Neill and Shaha, 2013).

Section snippets

Poorly differentiated and anaplastic thyroid carcinoma

Since Sakamoto et al. (1983) first described PDTC, there has been contention regarding its characterization and diagnosis (Sakamoto et al., 1983). Currently, several distinct criteria for diagnosing PDTC are in use. The 2004 World Health Organization Classification of Tumors describes PDTC as, “… follicular-cell neoplasms that show limited evidence of structural follicular cell differentiation and occupy both morphologically and behaviorally an intermediate position between differentiated

Dysregulated signaling pathways in PDTC and ATC

WDTCs commonly exhibit dysregulated activity of the mitogen-activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase (PI3K) signaling pathway, or a combination of the two (Liu et al., 2008, Wang et al., 2007, Hou et al., 2007). These alterations occur through direct genomic/epigenomic mutations or indirectly via epigenetic deregulation (Eze et al., 2011, Vu-Phan and Koenig, 2014, Faam et al., 2015). Although the molecular basis for disease progression from WDTC to PDTC and/or ATC

Epigenetic mechanisms and classifications in cancer

Tightly controlled epigenetic regulation is essential for normal growth, development, acquisition, and maintenance of unique functions of organs and organ systems. Deregulation of epigenetic controls, on the other hand, may play crucial roles in the origin and/or progression of various disease processes including cancer. Cancer-specific, as well as global epigenetic aberrations, are reported in a variety of malignancies including thyroid cancers (Rodriguez-Rodero et al., 2014). The four major

Epigenetic modifications in thyroid cancer

Aberrant DNA methylation leading to the activation of proto-oncogenes or silencing of tumor suppressor genes, is common in thyroid tumors. Tumor suppressor genes that are epigenetically inactivated in thyroid cancers include DAPK, PTEN, RASSF1A, RAPβ2, RAP1GAP, SLC5A8, and TIMP3 (Faam et al., 2015). Aberrant promotor methylation of TIMP3, SLC5A8, DAPK, and RARb2 also overlap with BRAF mutations in PTC and may contribute to the tumor behavior (Hu et al., 2006, Xing et al., 2003). The PTEN

Characterization of PDTC and ATC epigenomes

Recent comprehensive genetic and epigenetic analyses of PTC and FTC helped to generate a better understanding of their respective epigenomes (Hou et al., 2007, Eze et al., 2011, Vu-Phan and Koenig, 2014, Faam et al., 2015, Xing, 2013, Kunstman et al., 2015, Rodriguez-Rodero et al., 2014, Feinberg et al., 2016, Schagdarsurengin et al., 2002, Kondo et al., 2009, Schagdarsurengin et al., 2010, Catalano et al., 2012b, Russo et al., 2011). Although next-generation genetic analysis of ATC revealed

Current status of epigenetic-targeted therapy in thyroid cancer

The drugs targeting epigenetic alterations in tumors can be classified according to the mechanism(s) that they target. HDAC inhibitors and DNA methylation inhibitors (DNMTi) are two main classes of epigenetic pharmaceuticals. To date, the US Food and Drug Administration (FDA) has approved four HDAC inhibitors including belinostat, panobinostat, romidepsin, and vorinostat for the treatment of hematologic malignancies (Lee et al., 2015, Lakshmaiah et al., 2014, De Souza and Chatterji, 2015, Jones

Future prospects for epigenetic-targeted therapy in PDTC and ATC

Currently, there are no thyroid-specific epigenetic medications available for the treatment of WDTC, PDTC, or ATC. However, multiple studies have recently demonstrated a progressive understanding of the nature of the epigenetic alterations in PDTC and ATC, potentially paving the way to the development of targeted epigenetic pharmaceuticals in the near future (Vu-Phan and Koenig, 2014, Faam et al., 2015, Xu and Ghossein, 2016, Landa et al., 2016, Kunstman et al., 2015, Rodriguez-Rodero et al.,

Conflict of interest

The authors have no actual or potential conflicts of interest to declare.

Acknowledgement

The authors thank Dr Ngoentra Tantranont for providing the histopathologic pictures of PDTC and ATC.

References (175)

S.T. Aherne et al.
Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression
Int. J. Mol. Med.
(2016)
F. Alvarez-Nunez et al.
PTEN promoter methylation in sporadic thyroid carcinomas. thyroid
Off. J. Am. Thyroid Assoc.
(2006)
P. Aragon Han et al.
MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: a systematic review. Thyroid
Off. J. Am. Thyroid Assoc.
(2015)
S. Asioli et al.
Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression
Mod. Pathol.
(2010)
E. Baldini et al.
Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines
Clin. Ter.
(2012)
D.P. Bartel
MicroRNAs: target recognition and regulatory functions
Cell
(2009)
E. Borbone et al.
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation
Oncogene
(2010)
E. Borbone et al.
Enhancer of zeste homolog 2 overexpression has a role in the development of anaplastic thyroid carcinomas
J. Clin. Endocrinol. Metab.
(2011)
M. Boufraqech et al.
miR30a inhibits LOX expression and anaplastic thyroid cancer progression
Cancer Res.
(2015)
M. Boufraqech et al.
MicroRNAs in the thyroid
Best. Pract. Res. Clin. Endocrinol. Metab.
(2016)

J. Braun et al.

Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas

Oncogene

(2010)

G.L. Brien et al.

Exploiting the epigenome to control cancer-promoting gene-expression programs

Cancer Cell.

(2016)

M.G. Catalano et al.

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo

Int. J. cancer J. Int. du cancer

(2012)

M.G. Catalano et al.

Epigenetics modifications and therapeutic prospects in human thyroid cancer

Front. Endocrinol. (Lausanne)

(2012)

Q. Cheng et al.

MiR-618 inhibits anaplastic thyroid cancer by repressing XIAP in one ATC cell line

Ann. Endocrinol. Paris.

(2014)

A.I. Damanakis et al.

MicroRNAs let7 expression in thyroid cancer: correlation with their deputed targets HMGA2 and SLC5A5

J. cancer Res. Clin. Oncol.

(2016)

C. De Souza et al.

HDAC inhibitors as novel anti-cancer therapeutics

Recent Pat. Anticancer Drug Discov.

(2015)

R.A.L.R. DeLellis

Heitz PU WHO Classification of Tumors, Pathology and Genetics-tumors of Endocrine Organs

(2004)

M.S. Dettmer et al.

MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights

J. Mol. Endocrinol.

(2014)

M. Duvic et al.

Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma

Clin. Lymphoma Myeloma

(2009)

F. Esposito et al.

Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2

J. Clin. Endocrinol. Metab.

(2012)

O.P. Eze et al.

The role of epigenetic alterations in papillary thyroid carcinogenesis

J. Thyroid. Res.

(2011)

B. Faam et al.

Epigenetic modifications in human thyroid cancer

Biomed. Rep.

(2015)

J.A. Fagin et al.

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas

J. Clin. Invest

(1993)

A.P. Feinberg et al.

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

Nat. Rev. Genet.

(2016)

P. Fenaux et al.

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study

Lancet Oncol.

(2009)

E. Ferretti et al.

Notch signaling is involved in expression of thyrocyte differentiation markers and is down-regulated in thyroid tumors

J. Clin. Endocrinol. Metab.

(2008)

F. Foss et al.

A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma

Br. J. Haematol.

(2015)

T. Frisk et al.

Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer

Genes Chromosomes Cancer

(2002)

F. Furuya et al.

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin

Endocrinology

(2004)

C.S. Fuziwara et al.

MicroRNA deregulation in anaplastic thyroid cancer biology

Int. J. Endocrinol.

(2014)

G. Garcia-Rostan et al.

Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma

Cancer Res.

(1999)

G. Garcia-Rostan et al.

Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis

Am. J. Pathol.

(2001)

G. Garcia-Rostan et al.

Mutation of the PIK3CA gene in anaplastic thyroid cancer

Cancer Res.

(2005)

K.P. Garnock-Jones

Panobinostat: first global approval

Drugs

(2015)

C. Geers et al.

Delta-like 4/Notch pathway is differentially regulated in benign and malignant thyroid tissues. thyroid

Off. J. Am. Thyroid Assoc.

(2011)

M.V. Geraldo et al.

MicroRNA miR-146b-5p regulates signal transduction of TGF-beta by repressing SMAD4 in thyroid cancer

Oncogene

(2012)

S.M. Glaser et al.

Anaplastic thyroid cancer: prognostic factors, patterns of care, and overall survival

Head neck

(2016)

V.L. Greenberg et al.

Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. Thyroid

Off. J. Am. Thyroid Assoc.

(2001)

A. Guerra et al.

Genet. Mutat. Treat. anaplastic thyroid cancer: a Syst. Rev. BMC Surg.

(2013)

C. Guo et al.

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation

Oncotarget

(2013)

R.A. Gupta et al.

Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

Nature

(2010)

A. Hebrant et al.

miRNA expression in anaplastic thyroid carcinomas

PLoS one

(2014)

S. Hemmer et al.

DNA copy number changes in thyroid carcinoma

Am. J. Pathol.

(1999)

D. Hiltzik et al.

Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients

Cancer

(2006)

P.L. Horn-Ross et al.

Continued rapid increase in thyroid cancer incidence in California: trends by patient, tumor, and neighborhood characteristics

Cancer Epidemiol. Biomarkers Prev.

(2014)

P. Hou et al.

Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clinical cancer research

Off. J. Am. Assoc. Cancer Res.

(2007)

P. Hou et al.

Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors

Cancer

(2008)

G.M. Howell et al.

RAS mutations in thyroid cancer

Oncology

(2013)

S. Hu et al.

Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer

Int. J. cancer J. Int. du cancer

(2006)

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Epigenetic modifications in poorly differentiated and anaplastic thyroid cancer

Highlights

Abstract

Introduction

Section snippets

Poorly differentiated and anaplastic thyroid carcinoma

Dysregulated signaling pathways in PDTC and ATC

Epigenetic mechanisms and classifications in cancer

Epigenetic modifications in thyroid cancer

Characterization of PDTC and ATC epigenomes

Current status of epigenetic-targeted therapy in thyroid cancer

Future prospects for epigenetic-targeted therapy in PDTC and ATC

Conflict of interest

Acknowledgement

Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression

Int. J. Mol. Med.

PTEN promoter methylation in sporadic thyroid carcinomas. thyroid

Off. J. Am. Thyroid Assoc.

MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: a systematic review. Thyroid

Off. J. Am. Thyroid Assoc.

Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression

Mod. Pathol.

Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines

Clin. Ter.

MicroRNAs: target recognition and regulatory functions

Cell

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

Oncogene

Enhancer of zeste homolog 2 overexpression has a role in the development of anaplastic thyroid carcinomas

J. Clin. Endocrinol. Metab.

miR30a inhibits LOX expression and anaplastic thyroid cancer progression

Cancer Res.

MicroRNAs in the thyroid

Best. Pract. Res. Clin. Endocrinol. Metab.

Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas

Oncogene

Exploiting the epigenome to control cancer-promoting gene-expression programs

Cancer Cell.

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo

Int. J. cancer J. Int. du cancer

Epigenetics modifications and therapeutic prospects in human thyroid cancer

Front. Endocrinol. (Lausanne)

MiR-618 inhibits anaplastic thyroid cancer by repressing XIAP in one ATC cell line

Ann. Endocrinol. Paris.

MicroRNAs let7 expression in thyroid cancer: correlation with their deputed targets HMGA2 and SLC5A5

J. cancer Res. Clin. Oncol.

HDAC inhibitors as novel anti-cancer therapeutics

Recent Pat. Anticancer Drug Discov.

Heitz PU WHO Classification of Tumors, Pathology and Genetics-tumors of Endocrine Organs

MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights

J. Mol. Endocrinol.

Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma

Clin. Lymphoma Myeloma

Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2

J. Clin. Endocrinol. Metab.

The role of epigenetic alterations in papillary thyroid carcinogenesis

J. Thyroid. Res.

Epigenetic modifications in human thyroid cancer

Biomed. Rep.

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas

J. Clin. Invest

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

Nat. Rev. Genet.

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study

Lancet Oncol.

Notch signaling is involved in expression of thyrocyte differentiation markers and is down-regulated in thyroid tumors

J. Clin. Endocrinol. Metab.

A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma

Br. J. Haematol.

Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer

Genes Chromosomes Cancer

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin

Endocrinology

MicroRNA deregulation in anaplastic thyroid cancer biology

Int. J. Endocrinol.

Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma

Cancer Res.

Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis

Am. J. Pathol.

Mutation of the PIK3CA gene in anaplastic thyroid cancer