High YEATS4 expression characterizes MDM2-amplified liposarcoma

Abstract

YEATS4 resides within the 12q13-15 chromosomal region, where it is frequently co-amplified with MDM2 and CDK4 in liposarcomas (LPS). However, its independent role in LPS progression and dedifferentiation remains poorly defined. In this study, YEATS4 expression was analyzed in 57 formalin-fixed paraffin-embedded (FFPE) LPS samples using quantitative real-time PCR and compared across histological subtypes. MDM2 amplification status was determined by fluorescence in situ hybridization (FISH). The functional relevance of YEATS4 was assessed via siRNA-mediated knockdown in two well-differentiated LPS (WDLPS) cell lines, GOT-3 and 93T449. Relative YEATS4 mRNA expression was significantly higher in MDM2-positive compared to MDM2-negative tumors (median = 0.413 vs. 0.007; p = 0.008). Using the median YEATS4 expression value (0.227) - calculated from WDLPS and DDLPS cases only - as a threshold, high YEATS4 expression was observed in 64% of high-grade dedifferentiated LPS (DDLPS), 54% of low-grade DDLPS, and 29% of WDLPS cases (p = 0.302). Functionally, YEATS4 silencing significantly reduced cell viability in 93T449 cells at Days 5 (24.1%) and Day 7 (22.1%) compared to control (p < 0.001). In GOT3 cells, a slight reduction was noted at Day 3 (7.6%) which was not sustained. In summary, YEATS4 could contribute to LPS progression in a subset of MDM2-amplified tumors, particularly in high-grade DDLPS. Its variable functional impact across models highlights the complexity of the 12q13-15 amplicon and supports further investigation into YEATS4 as a potential molecular marker and therapeutic target in LPS.

Keywords: MDM2; YEATS4; liposarcoma; real-time PCR.