TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer

Robert M. Witwicki, Muhammad B. Ekram, Xintao Qiu, Michalina Janiszewska, Shaokun Shu, Mijung Kwon, Anne Trinh, Elizabeth Frias, Nadire Ramadan, Greg Hoffman, Kristine Yu, Yingtian Xie, Gregory McAllister, Rob McDonald, Javad Golji, Michael Schlabach, Antoine deWeck, Nicholas Keen, Ho Man Chan, David RuddyTomas Rejtar, Sosathya Sovath, Serena Silver, William R. Sellers, Zainab Jagani, Michael D. Hogarty, Charles Roberts, Myles Brown, Kimberly Stegmaier, Henry Long, Ramesh A. Shivdasani, David Pellman, Kornelia Polyak

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Perturbed epigenomic programs play key roles in tumorigenesis, and chromatin modulators are candidate therapeutic targets in various human cancer types. To define singular and shared dependencies on DNA and histone modifiers and transcription factors in poorly differentiated adult and pediatric cancers, we conducted a targeted shRNA screen across 59 cell lines of 6 cancer types. Here, we describe the TRPS1 transcription factor as a strong breast cancer-specific hit, owing largely to lineage-restricted expression. Knockdown of TRPS1 resulted in perturbed mitosis, apoptosis, and reduced tumor growth. Integrated analysis of TRPS1 transcriptional targets, chromatin binding, and protein interactions revealed that TRPS1 is associated with the NuRD repressor complex. These findings uncover a transcriptional network that is essential for breast cancer cell survival and propagation. Witwicki et al. use a targeted shRNA screening strategy to identify transcriptional and epigenomic dependencies in poorly differentiated human cancers. TRPS1 is a lineage-specific transcription factor that is required for mitosis in breast cancer cells. TRPS1 is associated with the NuRD complex, and it regulates cell adhesion, cytoskeleton, and G2-M phase-related genes.

Original languageEnglish
Pages (from-to)1255-1267.e5
JournalCell Reports
Volume25
Issue number5
DOIs
StatePublished - 30 Oct 2018

Keywords

  • Lineage dependency
  • NuRD complex
  • TRPS1
  • breast cancer
  • mitosis
  • shRNA screen
  • transcriptional repressor

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