LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma

Abstract

Papillary thyroid carcinoma (PTC) is one of the most common kinds of endocrine-related cancer and has a heterogeneous prognosis. Metabolic reprogramming is one of the hallmarks of cancers. Aberrant glucose metabolism is associated with malignant biological behavior. However, the functions and mechanisms of glucose metabolism genes in PTC are not fully understood. Thus, data from The Cancer Genome Atlas database were analyzed, and lactate dehydrogenase A (LDHA) was determined to be a potential novel diagnostic and therapeutic target for PTCs. The research objective was to investigate the expression of LDHA in PTCs and to explore the main functions and relative mechanisms of LDHA in PTCs. Higher expression levels of LDHA were found in PTC tissues than in normal thyroid tissues at both the mRNA and protein levels. Higher expression levels of LDHA were correlated with aggressive clinicopathological features and poor prognosis. Moreover, we found that LDHA not only promoted PTC migration and invasion but also enhanced tumor growth both in vitro and in vivo. In addition, we revealed that the metabolic products of LDHA catalyzed induced the epithelial–mesenchymal transition process by increasing the relative gene H3K27 acetylation. Moreover, LDHA knockdown activated the AMPK pathway and induced protective autophagy. An autophagy inhibitor significantly enhanced the antitumor effect of FX11. These results suggested that LDHA enhanced the cell metastasis and proliferation of PTCs and may therefore become a potential therapeutic target for PTCs.

The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression

“…The gap between LDHA and EMT was bridged by a study showing that high levels of LDHA lead to increased levels of acetyl-CoA, which increased the histone acetylation of EMT-related genes, including CTNNB1 , RHOB , and TGFβR1 , thus, promoting EMT ( Figure 4 ) [ 192 ]. LDHA ↑ ⇒ acetyl-CoA ↑ ⇒ CTNNB1, RHOB, TGFβ R1 ↑ ⇒ EMT …”

Metabolic Reprogramming in Thyroid Cancer: Role of the Epithelial-Mesenchymal Transition

“…In fact, knockdown experiments in PTC cell lines revealed that LDHA promotes the transcription of EMT-related genes, including catenin beta 1 (CTNNB1), ras homologue family member B (RHOB) and TGF receptor 1 (TGFR1), to promote migration and invasion. The mechanism involves the release of intracellular acetyl-CoA, which enhances the histone acetylation of these EMT-related genes [46]. Consistent with these results, another study showed that LDHA and glycolysis were critical for PTC progression [70].…”

“…LDHA expression levels, in particular, positively correlate with the tall cell variant, which has a more aggressive clinical behavior compared with the classical PTCs and the more advanced tumor-node-metastasis (TNM) stage. Consistently, in 185 PTCs analyzed by immunohistochemistry, high expression levels of LDHA were associated with aggressive clinicopathological features and poor prognosis, and LDHA expression level resulted an independent prognostic marker for PTCs as it is the TNM stage [46].…”

Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment

“…reported that LDHA not only promoted PTC tumorigenesis but also migration and invasion by regulating autophagy and inducing EMT gene transcription. Moreover, they also found that the metabolic products catalyzed by LDHA increased the acetylation of the related H3K27 and induced EMT ( 32 ). LDHA is phosphorylated by HER2 and SRC39, resulting in the increased invasive and metastatic potential of head and neck cancer ( 33 ).…”

“…In conclusion, the expression of metabolism-related molecules revealed the differences in invasiveness and prognosis between different TC subtypes ( Figure 4 ). Numerous studies have demonstrated the relationship between the prognosis of thyroid carcinoma and glycolysis-related proteins such as GLUT, LDHA, MCT1 ( 32 , 135 , 136 ). Some studies have indicated that GLUT contributed to the increased glucose uptake observed during carcinogenesis ( 135 , 137 ).…”