Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells

Seung Ho Shin, Ji Su Lee, Jia Min Zhang, Sungbin Choi, Zarko V. Boskovic, Ran Zhao, Mengqiu Song, Rui Wang, Jie Tian, Mee Hyun Lee, Jae Hwan Kim, Minju Jeong, Jung Hyun Lee, Michael Petukhov, Sam W. Lee, Sang Gyun Kim, Lee Zou, Sanguine Byun

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.

Original languageEnglish
Article numberaay9131
JournalScience Advances
Volume6
Issue number31
DOIs
Publication statusPublished - 2020 Jul

Bibliographical note

Funding Information:
This research was funded by NIH grant 1RO1CA142805 to S.W.L. and National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2017R1C1B1006072) to S.B.

Publisher Copyright:
© 2020 The Authors.

All Science Journal Classification (ASJC) codes

  • General

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