YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells

Cancer Res. 2018 Jan 1;78(1):168-181. doi: 10.1158/0008-5472.CAN-17-0836. Epub 2017 Nov 27.

Abstract

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.Significance: These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. Cancer Res; 78(1); 168-81. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cisplatin / administration & dosage
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Transcription Factors
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*
  • Urothelium / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Deoxycytidine
  • gemcitabine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Cisplatin