The knock-down of overexpressed EZH2 and BMI-1 does not prevent osteosarcoma growth

Abstract

Abstract. Polycomb group proteins control the transcriptional memory of cells by maintaining the stable silencing of specific sets of genes through chromatin modifications. Polycomb group protein complexes control gene repression through recruitment of histone deacetylase. This recruitment leads to trimethylation of Lys 27 of histone H3 (H3K27). Histone H3K27 trimethylation is a property of stably silenced heterochromatin. EZH2 and BMI-1 are pivotal components of polycomb group protein complexes. Increased EZH2 levels have been found in several malignancies and reported as a molecular biomarker of poor prognosis. Similarly, BMI-1 has also been found to be associated with malignant transformation. In addition, inhibition of EZH2 or BMI-1 inhibits the growth of various types of malignancies. The expression of BMI-1 and EZH2 in human osteosarcoma has not been clearly determined. We examined the potential involvement of aberrant polycomb group protein expression in the pathogenesis of osteosarcoma. Real-time PCR revealed that expression of EZH2 in 143B, HOS, NOS-1 and Saos2 was increased compared to normal osteoblasts. BMI-1 was also up-regulated in 143B, HOS and NOS-1. Expression of EZH2 and BMI-1 were up-regulated in osteosarcoma patient biopsy specimens compared to normal bone. Immunohistochemical examinations showed that EZH2 and BMI-1 were up-regulated in osteosarcoma cells and that trimethylation of histone H3K27 was increased. We examined the effects of knock down of EZH2 and BMI-1 by shRNA. Unexpectedly, the knock-down of EZH2 and BMI-1 did not prevent osteosarcoma growth either in vitro or in vivo. Our findings suggest that EZH2 and BMI-1 may be tumorassociated antigens of osteosarcoma, but are not useful molecular targets of osteosarcoma treatment.

Histone Deacetylase 4 Promotes Osteosarcoma Cell Proliferation and Invasion by Regulating Expression of Proliferating Cell Nuclear Antigen

“…In the event of DNA damage, some complexes are recruited to PCNA residues and cause monoubiquitination or polyubiquitination (12). Protein ubiquitination by SUMO is a specific pathway that is subject to strict temporal regulation, and thus, abnormalities in this protein degradation pathway may be associated with malignant tumors (13, 14). Some studies demonstrate that PCNA expression is increased with the malignancy of OS and that decreasing PCNA expression can inhibit the proliferation of OS cells (15, 16).…”

PP2A inhibitor SET promotes mTORC1 and Bmi1 signaling through Akt activation and maintains the colony-formation ability of cancer cells

“…Bmi-1 forms polycomb repressive complex 1 (PRC1) with Ring1B and other proteins, which functions as a ubiquitin ligase for histone H2A and induces H2A monoubiquitination to lock chromatin in a silenced state ( 14 ). Elevated levels of Bmi-1 protein have been detected in various cancer types, including osteosarcoma ( 15 , 16 , 17 ). Bmi-1 promotes cancer stemness not only as a subunit of PRC1 but also in a PRC1-independent manner ( 18 , 19 , 20 , 21 , 22 ).…”