Zijian Tang

Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), remains one of the most aggressive primary brain tumors, and its proteostasis machinery represents a potential therapeutic target. Here we identify HSP27 as a key regulator-associated proteostasis in glioblastoma, IDH-wildtype, where it is linked to protein synthesis, folding, stress-granule dynamics and ubiquitin-mediated turnover. Ribo-seq showed HSP27 depletion reduced global protein synthesis, while TME labeling coupled to mass spectrometry revealed increased accumulation of unfolded proteins, indicating proteotoxic stress. Proteomic analysis of isolated stress granules (SGs) revealed enhanced sequestration of translational regulators, including EIF4E, mTOR, EIF3M and QKI, into stress granules (SGs), thereby reinforcing translational repression. Ubiquitinome profiling further revealed increased ubiquitination and proteasome-dependent loss of oncogenic and translational regulators, including AKT2, PARP1, EIF4G1, EIF4A3, and DDX5. Functionally, targeting HSP27 inhibits tumor growth and sensitizes glioblastoma to translational blockade. In orthotopic models, antisense oligonucleotide targeting HSP27 in combination with Didemnin B suppressed tumor progression and prolonged survival compared with either single agent. These findings associate HSP27 with proteostasis in glioblastoma, IDH-wildtype, and suggest HSP27-dependent proteostasis buffering as a therapeutic vulnerability.

Prostate cancer cells exhibit heightened transcriptional activity to sustain their aggressive phenotype, yet this creates DNA topological stress, leading to RNA: DNA hybrids (R-loops) and DNA damage that compromise genomic stability. LSH, an SNF2-family chromatin remodeler, is frequently dysregulated in cancers and linked to tumor progression, but its mechanistic role in genome maintenance remains unclear. Here, we demonstrate that LSH resolves R-loops in an ATP-dependent manner, mitigating transcription- replication (TR) conflicts in prostate cancer cells. LSH depletion caused R- loop accumulation due to reduced FANCD2 recruitment, exacerbating DNA damage and impairing Rad51 filament formation. Strikingly, LSH deficiency also increased R-loops at promoters of MYC and E2F target genes, stalling RNA polymerase II elongation and disrupting transcriptional programs critical for proliferation. Our findings reveal LSH is a key guardian of genome integrity, resolving R-loops to prevent TR conflicts and maintaining DNA repair fidelity. By linking LSH to R-loop resolution and transcriptional regulation, this study reveals its dual role in prostate cancer pathogenesis— supporting malignant proliferation while safeguarding genomic stability. These insights nominate LSH as a potential therapeutic target to disrupt oncogenic transcription and induce synthetic lethality in prostate cancer.