Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma

Abstract

The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3.

Histone methyltransferase SUV39H2 serves oncogenic roles in osteosarcoma

“…A limited number of studies have indicated that it may be plausible that targeting abnormal HMTs and HDMTs in cancer cells may partly contribute to the treatment of osteosarcoma. For example, EZH2 methyltransferase, which trimethylates H3K27 serves oncogenic roles in human osteosarcoma (6), and treatment with EZH2 inhibitor leads to a marked reduction of cell viability in osteosarcoma (34); increased expression of the HMT NSD3 has been observed in osteosarcoma, and NSD3 is likely to serve key roles in the development of osteosarcoma (8). Another study reported that LSD1 is overexpressed in osteosarcoma, and treatment of osteosarcoma cells with the LSD1 inhibitor tranylcypromine reduced cell growth (35).…”

“…A recent study demonstrated that histone methylation, a mechanism for modifying chromatin structure, contributes to aberrant transcriptional regulation and oncogenic signaling pathways in osteosarcoma (4). Furthermore, increased expression of histone methyltransferases (HMTs), including G9a, enhancer of zeste homolog 2 (EZH2), nuclear SET domain-containing 3 (NSD3), protein arginine N-methyltransferase 1, and coactivator-associated arginine methyltransferase 1, contribute to osteosarcoma development (5)(6)(7)(8)(9)(10). These data suggested that genes encoding histone methylation modifiers, HMTs and histone demethylases (HDMTs), may serve key roles in the development and progression of OS.…”

RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma

“…Samples containing >50% of RanBP9 or TSSC3-positive cells were designated as 'positive expression'. 48, 49, 50 Lung metastases and local recurrence were diagnosed by both imaging and pathology, and the surgical margins were classified according to the Enneking staging system. Patients with primary osteosarcoma were classified as with or without metastasis at diagnosis.…”

Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment

“…Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2. The knockdown of EZH2 caused a decrease in anti-apoptotic Bcl-2 and an increase in pro-apoptotic Bax and Bak proteins, as well as an increase in the expression of cytochrome C in the cytosol; indicating that EZH2 suppressed cell apoptosis through the intrinsic apoptotic pathway [77]. Additionally, EZH2 could inhibit cell apoptosis by coordinating the epigenetic silencing of two proapoptotic microRNAs (miRNA), miR-205 and miR-31 [78].…”