PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance

Tabury, K.; Monavarian, M.; Listik, E.; Shelton, A. K.; Choi, A. S.; Quintens, R.; Arend, R. C.; Hempel, N.; Miller, C. R.; Györrfy, B.; Mythreye, K.

doi:10.1101/2022.01.11.475893

bioRxiv · 10.1101/2022.01.11.475893

PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance

Tabury, K.·Monavarian, M.·Listik, E.·Shelton, A. K.·Choi, A. S.·Quintens, R.·Arend, R. C.·Hempel, N.·Miller, C. R.·Györrfy, B.·Mythreye, K.

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Abstract

Metastatic growth of ovarian cancer cells into the peritoneal cavity requires adaptation to various cellular stress factors to facilitate cell survival and growth. Here we demonstrate the role of PVT1, one such stress induced long non-coding RNA, in ovarian cancer growth and metastasis. PVT1 is an amplified and overexpressed lncRNA in ovarian cancer with strong predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by ovarian tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1 dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation models in vivo. We find that reducing PVT1 causes widespread transcriptome changes leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which directly impacts chemosensitivity. Together, these findings implicate PVT1 as a promising therapeutic target to suppress metastasis and avoid chemoresistance in ovarian cancer. SUMMARY BLURBPVT1 is a stress-responsive IncRNA regulated by YAP1, leading to increased ovarian cancer metastasis and chemoresistance, making PVT1 a promising therapeutic target.

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Tabury, K., Monavarian, M., Listik, E., Shelton, A. K., Choi, A. S., Quintens, R., Arend, R. C., Hempel, N., Miller, C. R., Györrfy, B., Mythreye, K.. 2022-01-13. PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance. https://doi.org/10.1101/2022.01.11.475893

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