Multi-Omic Analyses Reveal VPS72 Associations with Chromatin Remodeling, Proliferation, and Stress-Response Programs...

Malignant cells hijack epigenetic processes to sustain proliferation and to tolerate stressors that would otherwise limit cell growth, yet the chromatin remodeling activities that establish and maintain these programs are poorly defined. H2A.Z is a histone variant deposited into nucleosomes by the SRCAP and TIP60 chromatin-remodeling complexes, which share VPS72 as a chaperone subunit. VPS72 is located at 1q21, a region recurrently gained in human cancers, yet its contribution to tumor biology remains largely unexplored. Here, we show that VPS72 copy-number gain occurs in more than one-third of tumors and its expression is enriched beyond that expected from neighboring 1q21 genes and remains elevated over normal tissue in copy-neutral tumors. Across cancer types, higher VPS72 expression was associated with proliferative transcriptional programs, cell-cycle-related chromatin accessibility, and genomic instability. Single-cell analyses localized these associations primarily to malignant cells. Higher VPS72 expression and copy-number gain were associated with shorter overall survival in several solid tumors, although these relationships varied by lineage. VPS72 copy-number gain was also associated with shorter overall survival after adjustment for age and sex. Cancer-cell screens further identified recurrent VPS72 dependency, and VPS72 depletion suppressed proliferative programs while inducing stress, inflammatory, and apoptotic responses that were only partly shared with H2A.Z depletion. Together, these findings identify VPS72 as a recurrently altered component of tumor chromatin regulation associated with proliferative and stress-response states and support further investigation of its therapeutic significance.