Biology subjects

Soto-Feliciano, Y.

Publications and source records attributed to Soto-Feliciano, Y..

4 recordsLinked to original sources

bioRxiv2026

Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System

Somatic mutations rewire the ubiquitin-proteasome system (UPS) to support tumor growth, but the proteome-wide consequences of cancer-driver alterations on UPS composition remain incompletely understood. Using harmonized proteogenomic data from up to 11 CPTAC cohorts, we performed an integrated pan-cancer analysis of UPS protein dysregulation, prognostic associations, and mutation-driven remodeling. We show that mRNA poorly predicts UPS protein abundance, that a defined set of E3 ligases is recurrently dysregulated across cancers, and that somatic mutations (most strikingly TP53 loss) produce coherent UPS protein-quantitative trait locus (pQTL) signatures. Two case studies (UBR5 and TRIM28) illustrate orthogonal modes of UPS rewiring: a mutation-driven axis in which TP53-mutant tumors elevate UBR5 to support replication stress tolerance, and a lineage-driven axis in which TRIM28 engages tissue-restricted regulatory networks with opposing prognostic effects in glioblastoma versus head and neck cancer. Each axis exposes context-specific therapeutic vulnerabilities, including sensitivity to DNA damage response inhibitors (UBR5-high) and lineage-specific drug responses (TRIM28-high). Together, these analyses define a mechanistic framework for how cancer-driver mutations reshape proteostasis through the UPS and nominate mutation- and lineage-defined dependencies for precision degrader therapy. The harmonized pan-tissue atlas and the UbiDash interactive resource that underpin parts of this analysis are reported in our companion paper1. HighlightsO_LIProteome-centric profiling reveals UPS dysregulation invisible at the transcript level across human cancers C_LIO_LIPan-cancer differential expression identifies recurrently dysregulated E3 ligases with prognostic value C_LIO_LIGenome-wide pQTL analysis uncovers mutation-driven UPS remodeling, with TP53 loss as a dominant driver C_LIO_LIUBR5 and TRIM28 define orthogonal mutation- and lineage-driven axes of UPS rewiring with distinct therapeutic vulnerabilities C_LI

systems biology↗

bioRxiv2026

PRMT5 inhibitors actively promote metastatic progression of lung adenocarcinoma

Epigenetic changes are a major driver of cancer progression, placing considerable focus on epigenetic regulators as therapeutic targets. Protein arginine methyltransferase 5 (PRMT5) is one such regulator, and numerous PRMT5 inhibitors (PRMT5i) in clinical trials. Despite this, the mechanisms and consequences of PRMT5i-resistance are unknown. Here, we demonstrate that aggressive cancer progression is an inbuilt feature of PRMT5i-resistance acquisition in lung adenocarcinoma (LUAD). Independently-generated resistant cell lines gain dedifferentiation signatures that typify late-stage disease and show increased metastatic potential in vivo. We establish that these state shifts are a direct consequence of PRMT5i action; treatment induces rapid and widespread chromatin rewiring, enabling derepression of late-stage disease states that are stably established in resistant cells. Notably, treatment of lung tumor-bearing mice drives rapid disease advancement without decreasing tumor burden, showing that drug-induced disease progression supersedes any benefits from PRMT5 inhibition in vivo. Furthermore, analyses of human cell lines and patient cohorts supports the notion of PRMT5 inhibition-mediated dedifferentiation. Collectively our data show that PRMT5i can actively promote self-resistance and disease progression in different tumor types. This raises serious concerns for the use of PRMT5i in patients, arguing that clinical studies should consider the possibility of drug-induced plasticity, resistance, and disease advancement.

cancer biology↗

bioRxiv2025

The conserved N-terminal SANT1-binding domain (SBD) of EZH2 Regulates PRC2 Activity

Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb Repressive Complex 2 (PRC2) methyltransferase a key regulator of cell differentiation, identity and plasticity. Consequently, extensive somatic mutations in PRC2, including gain- or loss- of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its EZH2 (Enhancer of Zeste Homolog 2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the non-catalytic EZH2 N-terminal SANT-Binding Domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigate how the SBD regulates PRC2 function. The domain is highly conserved in metazoans, dispensable for PRC2 assembly and chromatin localization, yet required for genome-wide histone H3K27 methylation. Further, we show that an intact SBD is necessary for the proliferation of EZH2- addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights to the regulation of PRC2 activity in normal development and malignancy.

genetics↗

bioRxiv2023

Specific cPRC1 complexes are co-opted to mediate oncogenic gene repression in diffuse midline glioma

Diffuse midline glioma (DMG) is a fatal childhood brain tumour characterised primarily by mutant histone H3 (H3K27M). H3K27M causes a global reduction in Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 by inhibiting PRC2 enzymatic activity. Paradoxically, PRC2 is essential in DMG tumour cells where residual complex activity is required for oncogenic gene repression, although the molecular mechanisms acting downstream of PRC2 in this context are poorly understood. Here, weve discovered this oncogenic gene repression is mediated by specific canonical PRC1 (cPRC1) formations. By combining CRISPR screening, biochemical and chromatin mapping approaches with functional perturbations we show that cPRC1 complexes containing CBX4 and PCGF4 drive oncogenic gene repression downstream of H3K27me3 in DMG cells. Remarkably, the altered H3K27me3 modification landscape characteristic of these tumours rewires the distribution of cPRC1 complexes on chromatin. CBX4 and PCGF4 containing cPRC1 accumulate at sites of H3K27me3 while other cPRC1 formations are displaced. Despite accounting for <5% of cPRC1 complexes in DMG, CBX4/PCGF4-containing complexes predominate as gene repressors. Our findings link the altered distribution of H3K27me3 with imbalanced cPRC1 function, promoting oncogenic gene repression in DMG cells, revealing new disease mechanisms and highlighting potential therapeutic opportunities in this incurable childhood brain tumour.

cancer biology↗