Posttranslational Modifications in Thyroid Cancer: Implications for Pathogenesis, Diagnosis, Classification, and Treatment

Abstract

There is evidence that posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, sumoylation, glycosylation, and succinylation, may be involved in thyroid cancer. We review recent reports supporting a role of posttranslational modifications in the tumorigenesis of thyroid cancer, sensitivity to radioiodine and other types of treatment, the identification of molecular treatment targets, and the development of molecular markers that may become useful as diagnostic tools. An increased understanding of posttranslational modifications may be an important supplement to the determination of alterations in gene expression that has gained increasing prominence in recent years.

Keywords: acetylation; glycosylation; methylation; post-translational modifications; protein; succinylation; sumoylation; thyroid cancer; ubiquitination.

Figure 1

The MAPK and related pathways in thyroid cancer. Shown in the (middle) of the figure is the classical MAPK pathway leading from an extracellular mitogenic stimulus that activates a receptor tyrosine kinase (RTK) in the cell membrane, to RAS, RAF (shown as BRAF-V600E), MEK and ERK. ERK enters the nucleus where it upregulates tumor-promoting genes and downregulates tumor suppressor genes and thyroid iodide-handling genes. On the (left) side of the figure is the nuclear factor-κB (NF-κB) pathway, in which extracellular stimuli activate the pathway, leading to activation of the inhibitor of κB (IκB) kinase (IKK), resulting in the phosphorylation of IκB. IκB becomes dissociated from NF-κB and then enters the nucleus to promote the expression of tumor-promoting genes. Through an undefined mechanism, BRAF-V600E promotes the phosphorylation of IκB and the release of NF-κB, thus activating the NF-κB pathway. Shown on the (right) side of the figure is the RASSF1–mammalian STE20-like protein kinase 1 (MST1)–forkhead box O3 (FOXO3) pathway. Activated by extracellular pro-apoptotic stimuli, RASSF1A activates MST1which phosphorylates FOXO3. The resulting phosphorylated FOXO3 becomes dissociated from 14-3-3 proteins and enters the nucleus to promote the expression of pro-apoptotic genes in the FOXO pathway. BRAF-V600E directly inhibits MST1 and prevents its activation by RASSF1A, thereby suppressing the pro-apoptotic signaling of the FOXO3 pathway. The downward arrow for the FOXO activities shown in the nucleus indicates this negative effect of BRAF-V600E on pro-apoptotic genes. DAPK1, death-associated protein kinase 1; HIF1A, hypoxia-inducible factor 1α; MMP, matrix metalloproteinase; NIS, sodium–iodide symporter; TGFB1, transforming growth factor β1; TIMP3, tissue inhibitor of metalloproteinases 3; TPO, thyroid peroxidase; TSHR, thyroid-stimulating hormone receptor; TSP1, thrombospondin 1; UPA, urokinase plasminogen activator; UPAR, urokinase plasminogen activator receptor; VEGFA, vascular endothelial growth factor A. Figure reprinted from Ref. [79], by permission.

Figure 2

The PI3K-AKT and related pathways in thyroid cancer. Extracellular signals activate receptor tyrosine kinases (RTKs), leading to the activation of RAS and PI3K. Activated PI3K catalyzes the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1; also known as PDPK1), which consequently associates with AKT and leads to phosphorylation (P) and the activation of AKT by PDK1. Phosphorylated AKT enters the nucleus, where it induces tumor-promoting genes. In the cytoplasm, phospho-AKT also activates other signaling molecules or pathways, including the mTOR pathway, which has an important role in tumorigenesis. Phospho-AKT can also directly phosphorylate glycogen synthase kinase 3β (GSK3β), relieving the GSK3β-mediated suppression of β-catenin. Consequently, β-catenin can enter the nucleus, where it promotes the expression of tumor-promoting genes. In the nucleus, phospho-AKT can phosphorylate forkhead box O3 (FOXO3) on its AKT-specific motif. This phosphorylated FOXO3 is translocated out of the nucleus to the cytoplasm, where it binds 14-3-3 proteins to be sequestered in the cytoplasm, thus terminating the pro-apoptotic activities of the FOXO3 pathway. The downward arrow for the FOXO activities in the nucleus in the figure indicates this negative effect of AKT on pro-apoptotic genes in the FOXO pathway, which would otherwise be upregulated by the FOXO3 pathway. The major negative regulatory mechanism of the PI3K–AKT pathway is PTEN, which is a phosphatase that converts PIP3 to PIP2, thus terminating the activation of the pathway. The inset shows the self-enhancement mechanism of PI3K–AKT signaling, resulting in a loss of termination of the signaling. Figure reprinted from Ref. [79], by permission.

Figure 3

The (upper) panel illustrates euchromatin (activating transcription) and the (lower) panel heterochromatin (inhibiting transcription). The round green symbol illustrates histone acetylation; the blue triangle illustrates active histone methylation; the red triangle illustrates repressive histone methylation; the blue round symbol illustrates DNA methylation. Figure reprinted from Ref. [99], by permission.

Figure 4

Glycoproteins are depicted containing Asn-linked (N-glycans) and Ser/Thr/Tyr-linked (S/T/Y) O-glycans. A membrane-bound glycoprotein is shown on the (left) and a soluble glycoprotein is on the (right). The monosaccharide residues (see the key) are added enzymatically to proteins in the endoplasmic reticulum (ER) and the Golgi apparatus by distinct enzymes.