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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 7 of 18

[100]
tumor cell proliferation and growth . Indeed, exogenous expression of THRB in human follicular thyroid
cancer (FTC) cells (FTC-133 and FTC-236) reduced cell proliferation and impaired cell migration through
inhibition of the PI3K-AKT-mTOR pathway. Further, in xenograft tumors, the re-expressed THRB
inhibited tumor growth and angiogenesis through suppression of vascular endothelial growth factor
(VEGF) signaling pathway . In these studies, how TRβ acted to converge these upstream signals to the
[100]
nuclear transcription was not clear. The elucidation of the underlying mechanisms awaits further in-depth
analysis. Nonetheless, these findings hold high promise that TRβ could be a potential therapeutic target for
thyroid cancer.

MYC and bromodomain and extra-terminal domain proteins
MYC is a master regulator of many fundamental processes such as cell cycle entry and progression,
ribosome biogenesis, and metabolism. In cancer, the MYC transcriptional network is frequently
overactivated through various mechanisms such as gene duplications, somatic mutations and chromosomal
translocations, which increase MYC stability, thereby allowing tumor initiation and progression. MYC is
overexpressed in more than half of all tumors and therefore has been regarded as one of the most important
oncogenes in cancer .
[108]

Uncontrolled expression of the MYC gene has been known to be responsible for the development and
progression of ATC [109,110] . MYC protein is frequently upregulated in ATC tumor tissues , and its high
[110]
expression has been associated with poor clinical outcome [111,112] . In a mouse model of ATC, high expression
[113]
of the MYC gene was related to thyroid cancer progression as indicated by the loss of differentiation . In a
mouse model of lung cancer, systemic inhibition of the MYC gene using a dominant negative MYC mutant
[114]
resulted in complete eradication of the lung cancers . However, so far, there has been no effective
approach to directly controlling the functions of the MYC protein itself.

Chromatin remodeling through histone acetylation plays a crucial role for the transcriptional control .
[115]
The bromodomain and extra-terminal domain (BET) family of proteins, such as bromodomain-containing
protein 4 (BRD4), interacts with the acetylated histones to recruit transcription activators and co-activators,
[116]
and chromatin complexes to particular promoter regions . Small-molecule inhibitors such as JQ1
selectively targeting this interaction between BET proteins and acetylated histones have been shown to
potently inhibit the MYC-mediated transcriptional program by attenuating super-enhancers in diverse
cancers [117-122] .

In thyroid cancer, JQ1 decreased MYC expression, induced cell cycle arrest, and suppressed tumor growth
in a xenograft mouse model [123,124] . In a preclinical mouse model of ATC (Thrb PV/PV Kras G12D [125]
) , JQ1 was
found to effectively suppress MYC expression and attenuate MYC-mediated transcriptional programs,
[125]
thereby inhibiting tumor growth and finally prolonging mice survival . The efficacy of JQ1 was further
tested in four cell lines originated from human ATC patients . JQ1 markedly inhibited tumor cell
[110]
proliferation through G0/G1 cell cycle arrest by suppressing MYC and inducing p21, p27, and RB
dephosphorylation. JQ1 also could impair cancer cell invasion through attenuation of epithelial-
mesenchymal transition (EMT) program. These in vitro findings were further confirmed by xenograft
studies showing that JQ1 inhibited the size and growth rate of tumor by suppressing p21-Cyclins/CDKs-Rb-
[110]
E2F signaling axis . All these findings collectively suggested that epigenetic action of JQ1 blocking the
interaction of BRD4 with histone acetyl-lysine sites across chromatin could suppress MYC transcription,
thereby interrupting ATC progression.