Abstract
H3K9me3 is enriched in DDLPS and represses the tumor suppressor KLF6 to promote aggressive disease.
Major finding: H3K9me3 is enriched in DDLPS and represses the tumor suppressor KLF6 to promote aggressive disease.
Mechanism: KLF6 inhibits DDLPS proliferation and induces the expression of adipogenesis differentiation genes.
Impact: H3K9me3 inhibition may be therapeutically beneficial in the aggressive DDLPS subtype.
Liposarcoma is among the most frequently diagnosed soft-tissue sarcomas, with two primary subtypes, well-differentiated (WDLPS) and dedifferentiated (DDLPS), being the most common. Although it is known that DDLPS carries a worse prognosis than WDLPS, the pathogenesis of these subtypes is poorly understood. To shed light on the contribution of epigenetic differences to the development of these LPS subtypes, Keung and colleagues performed an unbiased global analysis of nine common epigenetic marks across 151 LPS samples. DDLPS samples exhibited higher levels of histone H3 lysine 9 trimethylation (H3K9me3), which is associated with gene repression, compared with WDLPS. ChIP-sequencing analysis of 7 human WDLPS and DDLPS cell lines confirmed higher H3K9me3 levels in DDLPS. In particular, H3K9me3 was associated with genes involved in cellular differentiation and migration, suggesting that this repressive histone mark may regulate aggressiveness in LPS by blocking the maintenance of adipocyte differentiation. Among genes associated with increased H3K9me3 in DDLPS, the gene encoding the transcription factor Kruppel-like factor 6 (KLF6) was significantly underexpressed in DDLPS compared with WDLPS, suggesting that repression of KLF6 in DDLPS is a result of increased H3K9me3 at its associated regulatory regions. Overexpression of KLF6 in DDLPS cell lines decreased proliferation and invasiveness and delayed tumor onset in nude mice; these cells also displayed altered morphologic characteristics consistent with induction of adipocytic differentiation and senescence. In addition, overexpression of KLF6 increased the expression of proadipogenic factors, including peroxisome proliferator-activated receptor gamma, supporting a tumor-suppressive role for KLF6 in liposarcoma. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and global H3K9me3 levels and increased KLF6 expression, whereas KLF6 depletion ablated these effects. Overall, these data provide evidence that increased H3K9me3 levels promote the aggressive dedifferentiated phenotype of DDLPS via epigenetic silencing of KLF6 and suggest that H3K9me3 inhibition may be beneficial in LPS.
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