Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness

Abstract

Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.

Androgen receptor-dependent regulation of metabolism in high grade bladder cancer cells

“…FL-AR activity is further substantiated by the current study where depletion of the FL-AR elevates expression of multiple histone transcripts. The consequences of an abrupt elevation of multiple histones are not well studied, but in yeast abnormal histone accumulation interferes with chromosome segregation and promotes whole genome duplication 39 , while overexpression of replication-dependent histone genes confers malignancy to dedifferentiated liposarcoma 40 . Restraining FL-AR in the BlCa context may have similar consequences, but this needs to be further explored.…”

Nuclear High Mobility Group A2 (HMGA2) Interactome Revealed by Biotin Proximity Labeling

“…In glioma, a HMGA2/GCN5 protein complex promoted histone acetylation in nucleosomes at AT-rich DNA sites, to cause gene activation of matrix metalloproteinase 2 (MMP2), a mediator of invasiveness in glioma, and conferring a poor prognosis [ 80 ]. Overexpression of HMGA2 coincided with elevated levels of H2A, H2B, H3, and H4 core histones in a subpopulation of dedifferentiated liposarcoma, again conferring a poor prognosis [ 81 ]. An even more intricate HMGA2-histone relationship is suggested by recent evidence that demonstrates the requirement for HMGA2 to induce DNA nicks to facilitate the incorporation of phosphorylated H2A.XS139 isoform (γ-H2AX) into nucleosomes to earmark DNA sites for repair-mediated DNA demethylation and transcription activation [ 33 ].…”

Unraveling Histone Loss in Aging and Senescence

“…Using this model, the researchers effectively demonstrated that by inducing the expression of Yamanaka factors (OSK), they could successfully reprogram the epigenetic profile to resemble a more youthful state, thereby restoring the normal histone expression [30]. Together, these studies showed that certain regulatory factors play a central role in the expression of histone genes, and tweaking the expression of these master regulators could attenuate or accentuate the histone levels [60,[198][199][200][201].…”