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Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

Yicun Wang1,2, Jinhui Wu3, Hui Chen4

  • 1Department of Urology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002, China.

Science Advances
|February 11, 2021
PubMed

Insights

Kruppel-like factor 11 (KLF11) suppresses sarcoma cancer stem cells (CSCs). Loss of KLF11 promotes tumor growth and therapy resistance, but KLF11 can be pharmacologically reactivated to restore treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cancer stem cells (CSCs) drive tumor progression, recurrence, and treatment resistance.
  • Identifying regulators of sarcoma CSCs is crucial for developing effective therapies.

Purpose of the Study:

  • To identify key regulators of sarcoma CSCs.
  • To elucidate the role of Kruppel-like factor 11 (KLF11) in sarcoma CSC biology.
  • To explore KLF11 as a potential therapeutic target.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening in sarcoma cells.
  • In vitro and in vivo functional assays.
  • Mechanistic studies involving gene expression, protein interactions, and epigenetic analysis.
  • Analysis of patient data for KLF11 expression and clinical outcomes.

Main Results:

  • KLF11 was identified as a critical negative regulator of sarcoma CSCs.
  • KLF11 suppresses CSCs by forming a negative feedback loop with YAP/TEAD, which is epigenetically silenced in CSCs.
  • Epigenetic silencing of KLF11 leads to sustained YAP activation, promoting CSC characteristics.
  • Low KLF11 expression correlates with poor prognosis and reduced chemotherapy response in sarcoma patients.

Conclusions:

  • KLF11 acts as a tumor suppressor in sarcoma by inhibiting CSCs.
  • The KLF11-YAP/TEAD feedback loop is essential for controlling CSCs, and its disruption drives sarcoma progression.
  • Pharmacological activation of KLF11, for example, with thiazolidinediones, can restore chemotherapy sensitivity and represents a promising therapeutic strategy.

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