NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer

Alexander J. Cole; Mangala Iyengar; Santiago Panesso-Gómez; Patrick O'Hayer; Daniel Chan; Greg M. Delgoffe; Katherine M. Aird; Euisik Yoon; Shoumei Bai; Ronald J. Buckanovich

doi:10.1172/JCI.INSIGHT.131486

NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer

Alexander J. Cole, Mangala Iyengar, Santiago Panesso-Gómez, Patrick O'Hayer, Daniel Chan, Greg M. Delgoffe, Katherine M. Aird, Euisik Yoon, Shoumei Bai, Ronald J. Buckanovich

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

Development of chemotherapy resistance is a major problem in ovarian cancer. One understudied mechanism of chemoresistance is the induction of quiescence, a reversible nonproliferative state. Unfortunately, little is known about regulators of quiescence. Here, we identify the master transcription factor nuclear factor of activated T cells cytoplasmic 4 (NFATC4) as a regulator of quiescence in ovarian cancer. NFATC4 is enriched in ovarian cancer stem-like cells and correlates with decreased proliferation and poor prognosis. Treatment of cancer cells with cisplatin resulted in NFATC4 nuclear translocation and activation of the NFATC4 pathway, while inhibition of the pathway increased chemotherapy response. Induction of NFATC4 activity resulted in a marked decrease in proliferation, G₀ cell cycle arrest, and chemotherapy resistance, both in vitro and in vivo. Finally, NFATC4 drove a quiescent phenotype in part via downregulation of MYC. Together, these data identify NFATC4 as a driver of quiescence and a potential new target to combat chemoresistance in ovarian cancer.

Original language	English
Article number	e131486
Journal	JCI insight
Volume	5
Issue number	7
DOIs	https://doi.org/10.1172/JCI.INSIGHT.131486
Publication status	Published - 2020 Mar 17

Bibliographical note

Funding Information:
Funding for this work was provided by Ann and Sol Schreiber Mentored Investigator Award (599997) from the Ovarian Cancer Research Alliance, Department of Defense award W81XWH-15-1-0083, and NIH R01 award 1R01CA203810.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

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Medicine(all)

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10.1172/JCI.INSIGHT.131486

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title = "NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer",

abstract = "Development of chemotherapy resistance is a major problem in ovarian cancer. One understudied mechanism of chemoresistance is the induction of quiescence, a reversible nonproliferative state. Unfortunately, little is known about regulators of quiescence. Here, we identify the master transcription factor nuclear factor of activated T cells cytoplasmic 4 (NFATC4) as a regulator of quiescence in ovarian cancer. NFATC4 is enriched in ovarian cancer stem-like cells and correlates with decreased proliferation and poor prognosis. Treatment of cancer cells with cisplatin resulted in NFATC4 nuclear translocation and activation of the NFATC4 pathway, while inhibition of the pathway increased chemotherapy response. Induction of NFATC4 activity resulted in a marked decrease in proliferation, G0 cell cycle arrest, and chemotherapy resistance, both in vitro and in vivo. Finally, NFATC4 drove a quiescent phenotype in part via downregulation of MYC. Together, these data identify NFATC4 as a driver of quiescence and a potential new target to combat chemoresistance in ovarian cancer.",

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AU - Cole, Alexander J.

AU - Iyengar, Mangala

AU - Panesso-Gómez, Santiago

AU - O'Hayer, Patrick

AU - Chan, Daniel

AU - Delgoffe, Greg M.

AU - Aird, Katherine M.

AU - Yoon, Euisik

AU - Bai, Shoumei

AU - Buckanovich, Ronald J.

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PY - 2020/3/17

Y1 - 2020/3/17

N2 - Development of chemotherapy resistance is a major problem in ovarian cancer. One understudied mechanism of chemoresistance is the induction of quiescence, a reversible nonproliferative state. Unfortunately, little is known about regulators of quiescence. Here, we identify the master transcription factor nuclear factor of activated T cells cytoplasmic 4 (NFATC4) as a regulator of quiescence in ovarian cancer. NFATC4 is enriched in ovarian cancer stem-like cells and correlates with decreased proliferation and poor prognosis. Treatment of cancer cells with cisplatin resulted in NFATC4 nuclear translocation and activation of the NFATC4 pathway, while inhibition of the pathway increased chemotherapy response. Induction of NFATC4 activity resulted in a marked decrease in proliferation, G0 cell cycle arrest, and chemotherapy resistance, both in vitro and in vivo. Finally, NFATC4 drove a quiescent phenotype in part via downregulation of MYC. Together, these data identify NFATC4 as a driver of quiescence and a potential new target to combat chemoresistance in ovarian cancer.

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NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer

Abstract

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