Scholarlink

<p>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 <i>TP53</i> 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 <i>TP53</i>-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 paper [<CitationRef CitationID="CR1">1</CitationRef>].</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Pan-cancer proteogenomic interrogation of the ubiquitin-proteasome system

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月19日

查看全文
  • Tania J. González-Robles,
  • Maha Khan,
  • Paul Sastourné,
  • Marisa Triola,
  • Hua Zhou,
  • Yuki Kito,
  • Sharon Kaisari,
  • David Fenyö,
  • Gergely Rona,
  • Yadira M. Soto-Feliciano,
  • Benjamin G. Neel,
  • Kelly V. Ruggles,
  • Michele Pagano

摘要

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 paper [1].