TY - JOUR
T1 - The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17
AU - Chaves-Moreira, Daniele
AU - Mitchell, Marilyn A.
AU - Arruza, Cristina
AU - Rawat, Priyanka
AU - Sidoli, Simone
AU - Nameki, Robbin
AU - Reddy, Jessica
AU - Corona, Rosario I.
AU - Afeyan, Lena K.
AU - Klein, Isaac A.
AU - Ma, Sisi
AU - Winterhoff, Boris
AU - Konecny, Gottfried E.
AU - Garcia, Benjamin A.
AU - Brady, Donita C.
AU - Lawrenson, Kate
AU - Morin, Patrice J.
AU - Drapkin, Ronny
N1 - Funding Information:
L. Schwartz’s support and expertise. Funding: This work was supported by NIH SPORE in ovarian cancer P50 CA228991 (to R.D.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to R.D.), the Honorable Tina Brozman Foundation for Ovarian Cancer Research (to R.D.), the Basser Center for BRCA (to R.D.), the Claneil Foundation (to R.D.), NIH P01CA196539 (to B.A.G.), the Ann and Sol Schreiber Mentored Investigator Award (545754) from the Ovarian Cancer Research Alliance (to D.C.-M.), the Liz Tilberis Early Career Award (599175), also from the Ovarian Cancer Research Alliance (to K.L.), and a Research Scholars Grant from the American Cancer Society (to K.L.).
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved;
PY - 2022/4/5
Y1 - 2022/4/5
N2 - PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non–cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.
AB - PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non–cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.
UR - http://www.scopus.com/inward/record.url?scp=85127673719&partnerID=8YFLogxK
U2 - 10.1126/scisignal.abm2496
DO - 10.1126/scisignal.abm2496
M3 - Article
C2 - 35380877
AN - SCOPUS:85127673719
SN - 1945-0877
VL - 15
JO - Science signaling
JF - Science signaling
IS - 728
M1 - eabm2496
ER -