TY - JOUR
T1 - YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells
AU - Ooki, Akira
AU - Del Carmen Rodriguez Pena, Maria
AU - Marchionni, Luigi
AU - Dinalankara, Wikum
AU - Begum, Asma
AU - Hahn, Noah M.
AU - VandenBussche, Christopher J.
AU - Rasheed, Zeshaan A.
AU - Mao, Shifeng
AU - Netto, George J.
AU - Sidransky, David
AU - Hoque, Mohammad O.
N1 - Funding Information:
N.M. Hahn is a consultant/advisory board member for Genentech, BMS, AstraZeneca, Merck, Seattle Genetics, Pieris, Advanced Health, Rexahn, TransMed, TARIS. C.J. VandenBussche is a consultant at Personal Genome Diagnostics and reports receiving a commercial research grant from Sienna Cancer Diagnostics. Z.A. Rasheed works for Global Medical Affairs at AstraeZeneca. S. Mao has received speakers bureau honoraria from Bristol-Myers Squibb and is a consultant/advisory board member for Bayer and AstraZeneca. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was funded by Flight Attendant Medical Research Institute Young Clinical Scientist Award 052401 YCSA (to M.O. Hoque), Career Development award from SPORE in Cervical Cancer Grants P50 CA098252 (to M.O. Hoque), Allegheny Health Network-Johns Hopkins Cancer Research Fund 80039465 (to M.O. Hoque), P30CA006973 (to L. Marchionni), and 1R01CA163594-01 (to D. Sidransky and M.O. Hoque).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040129468&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040129468&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-0836
DO - 10.1158/0008-5472.CAN-17-0836
M3 - Article
C2 - 29180467
AN - SCOPUS:85040129468
SN - 0008-5472
VL - 78
SP - 168
EP - 181
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -