Over-methylation of Histone H3 Lysines Is a Common Molecular Change Among the Three Major Types of Soft-tissue Sarcoma in Patient-derived Xenograft (PDX) Mouse Models

Abstract

Background/Aim: Sarcomas are considered a heterogeneous disease with incomplete understanding of its molecular basis. In the present study, to further understand general molecular changes in sarcoma, patient-derived xenograft (PDX) mouse models of the three most common soft-tissue sarcomas: myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS) and liposarcoma were established and the methylation status of histone H3 lysine marks was studied. Materials and Methods: Immunoblotting and immunohistochemical staining were used to quantify the extent of methylation of histone H3K4me3 and histone H3K9me3. Results: In all 3 sarcoma types in PDX models, histone H3K4me3 and H3K9me3 were found highly overmethylated compared to normal muscle tissue. Conclusion: Histone H3 lysine over-methylation may be a general basis of malignancy of the major sarcoma types.

Reversion of methionine addiction of osteosarcoma cells to methionine independence results in loss of malignancy, modulation of the epithelial-mesenchymal phenotype and alteration of histone-H3 lysine-methylation

“…It was previously reported that methylation of histone H3 lysine marks in tumor-initiating cells was increased compared to non-tumor-initiating cells ( 11 ). Our previous studies also showed that histone-H3 lysine-methylation was increased in cancer cells compared to normal cells ( 12 , 23 ), and it is further increased in high-malignancy variants selected from parental cancer cells, compared to the parental cells ( 16 ). We also previously reported that the status of the histone-H3 lysine-methylation in methionine-addicted cancer cells is unstable during methionine restriction, using recombinant L-methionine α-deamino-γ-mercapto-methane lyase (rMETase) ( 24 ), at concentrations which arrest cancer-cell proliferation ( 12 , 14 ).…”

Extent and Instability of Trimethylation of Histone H3 Lysine Increases With Degree of Malignancy and Methionine Addiction

“…The present study demonstrates that methylation of H3K9me3 increases with malignancy as well as with methionine addiction starting from low-malignant lowmethionine-addiction revertant cells to high-malignancy high-methionine-addiction cells. These results suggest that methionine addiction is linked to overmethylation of H3K9me3 and both are linked to malignancy, suggesting methionine addiction and overmethylation are a fundamental basis of oncogenic transformation (14,(27)(28)(29).…”

“…Total histone H3 (1:5,000, 17168-1-AP; Proteintech, Rosemont, IL, USA) was used as a loading control. Previously-described techniques were used for histone extraction, immunoblotting and signal detection (17,(26)(27)(28).…”

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet

“…The present study suggests that methionine restriction is promising in combination with second-line chemotherapy for metastatic breast cancer and further clinical studies are needed. o-rMETase is effective as it targets the fundamental basis of cancer, methionine addiction (6)(7)(8)(9)(10)(11)(12)(13)(14)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”