Epigenetic Abnormalities in Chondrosarcoma

Abstract

In recent years, our understanding of the epigenetic mechanisms involved in tumor pathology has improved greatly. DNA and histone modifications, such as methylation, demethylation, acetylation, and deacetylation, can lead to the up-regulation of oncogenic genes, as well as the suppression of tumor suppressor genes. Gene expression can also be modified on a post-transcriptional level by microRNAs that contribute to carcinogenesis. The role of these modifications has been already described in many tumors, e.g., colorectal, breast, and prostate cancers. These mechanisms have also begun to be investigated in less common tumors, such as sarcomas. Chondrosarcoma (CS) is a rare type of tumor that belongs to sarcomas and is the second most common malignant bone tumor after osteosarcoma. Due to unknown pathogenesis and resistance to chemo- and radiotherapies of these tumors, there is a need to develop new potential therapies against CS. In this review, we summarize current knowledge on the influence of epigenetic alterations in the pathogenesis of CS by discussing potential candidates for future therapies. We also emphasize ongoing clinical trials that use drugs targeting epigenetic modifications in CS treatment.

Keywords: chondrosarcoma; epigenetic mechanisms; targeted therapy.

Figure 1

Epigenetic changes to histones in chondrosarcoma (CS). The mechanism of histone modification is still not fully understood; however, some proteins were observed to play a role in this process in CS. The methylation of histone H3 lysine K9 (H3H9), histone H3 lysine K4 (H3K4), and histone H3 lysine K27 (H3K27) appears to be independent of δ-2-hydroxyglutarate (2HG); however, the methylation of H3K27 is related to increased expression of enhancer of zeste homolog 2 (EZH2)—a part of the Polycomb Repressive Complex 2 (PRC2), together with Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 Protein Homolog (SUZ12). This process can be inhibited by 3-Deazaneplanocin A (DZNep). On the other hand, H3K4 and H3K9 demethylation (which leads to inactivation of the suppressor of cytokine signaling 3 (SOCS3) and ten-eleven translocation methylcytosine dioxygenase 1 and 2 (TET1/2)), is caused by the expression of histone lysine-specific demethylase 1 (LSD1). This can be inhibited by proline-rich polypeptide-1 (PRP-1). Lysine-specific demethylase 6A (KDM6A, UTX) and lysine demethylase 6B (KDM6B, JMJD3) decrease H3K27 methylation, which can be blocked by the GSK-J4 inhibitor in combination with cisplatin. Sirtuin1 (SIRT1) deacetylase deregulation can be blocked by resveratrol, while decreased acetylation of H3 and collagen alpha-1(II) chain (COL2A1) expression can be reversed by depsipeptide.