Page 66 - Read Online

Page 6 of 18 Lee et al. J Cancer Metastasis Treat 2021;7:27 https://dx.doi.org/10.20517/2394-4722.2021.58

Numerous studies have indicated transcriptional regulation is essential for maintaining ESC status. This
transcriptional regulation is mainly mediated by pluripotency TFs such as Oct4, Sox2, Nanog, and MYC.
Chromatin immunoprecipitation studies revealed extensive co-binding of Oct4, Sox2, and Nanog at many
active and silent genomic target regions in ESC, indicating their role in activating other pluripotency-related
factors and simultaneously suppressing lineage-specific genes [77,78] . While Oct4, Sox2 and Nanog cooperate
[79]
with the mediator complex to recruit RNA Pol II for gene transcription , MYC controls the transcriptional
pause release of RNA Pol II through p-TEFb and induces the stem cell-like state by epigenetic
[80]
reprograming . Interestingly, ESC-specific genes including the pluripotency TFs and their activation
[81]
targets are preferentially and frequently overexpressed in poorly differentiated aggressive human
cancers [82-84] . Furthermore, this ESC-like gene signature is associated with poor clinical outcomes in those
[82]
cancers, supporting existence of CSCs and their clinical significance . More importantly, the genome of
ESC is transcriptionally and globally hyperactive and undergoes large-scale silencing during differentiation.
This transcriptional hyperactivity in ESCs is mediated by aberrant expression of the general transcriptional
machinery and chromatin remodeling genes, indicating the global hyperactive transcription as a hallmark of
pluripotent ESC and CSC, contributing to their plasticity [85-89] . Therefore, targeting transcriptional regulators
would have clinical benefits for CSC depletion and re-differentiation in the treatment of ATC.

POTENTIAL OF TRANSCRIPTIONAL REGULATORS AS BIOMARKERS AND THERAPEUTIC
TARGETS IN ATC
Thyroid hormone nuclear receptors
Thyroid hormone nuclear receptors (TRs) are members of the nuclear receptor superfamily. They are
important signaling TFs to mediate biological actions of the thyroid hormone (T3) for development,
growth, and metabolic homeostasis [50,90] . TRs generally act as ligand-dependent TFs by binding to thyroid
hormone response elements (TREs) located in regulatory sites of their target genes , but they can also
[91]
control the expression of target genes that do not possess a TRE by interacting with other TFs [92,93] . Over the
past decades, there have been major advances in understanding the physiological functions of TRs at the
molecular level and, recently, their role in cancer biology. Previous studies have demonstrated that loss of
heterozygosity, deletion, and reduced expression of the THRB gene are associated with development of
diverse human cancers . In addition, the THRB gene is frequently silenced through hypermethylation of its
[94]
promotor region [95-101] or via microRNA-mediated mechanisms in various cancers including thyroid
[102]
cancer. These findings collectively suggest TR as a tumor suppressor. Surprisingly, a dominant-negative C-
terminal frameshift mutation of TRβPV (Thrb PV/PV mice) drives tumorigenesis in thyroid , mammary ,
[103]
[104]
and pituitary gland. These deleterious effects due to the loss of functional TRβ were clearly evident in that
[105]
TRβ mice and Thrα1 Thrb mice spontaneously developed metastatic follicular thyroid cancer .
[106]
[107]
PV/-
-/-
-/-
That the loss of functional TRβ led to cancer development suggested that TRs broadly control
transcriptional programs to suppress oncogenesis, raising the possibility that TRβ could be targeted for
treatment of thyroid cancer.
This therapeutic potential of TRβ was tested in human differentiated thyroid cancer (DTC) cells. Evaluation
of thyroid cancer specimens of patients and cancer cell lines showed that the expression of the THRB gene
was suppressed through its promoter hypermethylation . Further, the promoter hypermethylation level of
[101]
the THRB gene was positively correlated with thyroid cancer progression. When human thyroid cancer cell
lines in which the THRB gene was silenced through its promoter hypermethylation were treated with
demethylation agents, the THRB gene expression was reactivated, which suppressed cancer cell proliferation
and migration, and in vivo tumor growth in a xenograft model. These actions of the reactivated THRB gene
occurred through suppression of the β-catenin signaling pathway in thyroid cancer cell lines . These
[101]
findings led to the direct demonstration that the exogenous expression of the THRB gene could suppress