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Lee et al. J Cancer Metastasis Treat 2021;7:27 https://dx.doi.org/10.20517/2394-4722.2021.58 Page 5 of 18

itself have been identified, suggesting that coordinated alterations of transcriptional signals upstream of
[56]
RNA Pol II are more important for the neoplastic state . Chromatin regulators are important for efficient
delivery of transcriptional signals from enhancers to promoters. They function globally, and thus their
[56]
dysregulation can profoundly affect the gene expression program of cancer cells .

Recent studies have demonstrated that specific chromosomal structures play critical roles for gene
regulation. The term insulated neighborhoods was coined to indicate that genes and their regulatory
elements are typically regulated together within specific DNA loop structures. These chromosomal loop
structures are bound by the CTCF protein and are co-bound with the cohesin complex . These
[57]
chromosomal structures produce specific enhancer-gene interactions that are necessary for gene activation
and repression [58-60] . Therefore, mutations of proteins in the chromosome loop structures can profoundly
affect overall gene expression. According to recent cancer genome sequencing studies, somatic mutations in
the CTCF protein and the cohesion complex are frequently developed in various solid tumors, and these
mutations can modify the insulated neighborhoods all over the genome, thereby rendering chromatin more
accessible to oncogenic transcriptional signaling for carcinogenesis [61,62] .

There are classes of cis-regulatory elements that have significant roles in cancer biology: super-enhancers
and insulators that form the insulated neighborhoods. Super-enhancers are regions of the genome
comprising multiple enhancers and bind to high densities of transcriptional components to drive genes
involved in maintaining specific cell identities. Cancer cells attain super-enhancers for driving the
[63]
expression of oncogenes through various mechanisms [29,63,64] , including DNA translocation , focal
amplification , small insertions and deletions , and epigenomic mechanisms . Somatic mutations in
[67]
[66]
[65]
loop anchors of insulated neighborhoods around oncogenes also frequently occur in diverse cancers. Of
note, DNA-binding motif of the CTCF protein in loop anchor regions is one of the most frequently altered
TF-binding sequences in human cancer .
[68]
In addition, transcriptional dysregulations are known to be tightly linked to epigenetic alterations,
contributing to pervasive gene expression changes in cancer [69-71] . Epigenetic alterations are heritable and a
dynamic process, altering the phenotypes by dysregulating gene expression without changes in DNA
sequences. Epigenetic changes include DNA methylation, histone modifications, and the regulation of non-
[72]
coding RNA . These changes could lead to chromatin remodeling, resulting in profound changes of gene
[72]
expression profiles in cancer . This epigenetic regulation allows the genome-wide transcriptional
dysregulation independent of genetic change in cancer. Interestingly, the chromatin features of cell-of-
[73]
origin are known to be strong predictors for cancer mutation profiles , suggesting chromatin alterations as
critical drivers for cancer development.

Transcriptional Regulation for Maintaining Cancer Stem Cells
For effective targeting of transcription regulators for treatment of ATC, emerging knowledge about the roles
of cancer stem cells (CSCs) should be considered. The prevailing hypothesis has been that CSCs are
responsible for treatment resistance and tumor relapse in aggressive cancers including ATC. CSCs are a
subpopulation of cancer cells having features similar to normal embryonic stem cells (ESCs), such as self-
renewal ability and pluripotency . CSCs are endowed with the ability for self-renewal and for initiating
[74]
tumors at low cell density. They can also enable a considerable portion of tumor cells to be differentiated
according to tumor microenvironment. CSCs are more resistant than non-CSCs to anti-cancer therapy.
Such resistance enables CSCs to evolve in the clonal selection for aggressive phenotype [75,76] .