Abstract
Genome‐wide studies in tumor cells have indicated that chromatin‐modifying proteins are commonly mutated in human cancers. The lysine‐specific methyltransferase 2C (KMT2C/MLL3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT2C activity are deficient in homologous recombination‐mediated double‐strand break DNA repair. Consequently, these cells suffer from substantially higher endogenous DNA damage and genomic instability. Finally, these cells seem to rely heavily on PARP1/2 for DNA repair, and treatment with the PARP1/2 inhibitor olaparib leads to synthetic lethality, suggesting that cancer cells with low KMT2C expression are attractive targets for therapies with PARP1/2 inhibitors.
Synopsis
The histone methyltransferase KMT2C/MLL3 is commonly mutated in cancer and involved in the transcriptional regulation of several DNA repair genes. Its loss leads to increased DNA damage and dependence on PARP1/2.
KMT2C loss in bladder cancer cells affects the expression of DNA repair genes.
KMT2C loss leads to extensive chromosomal instability as well as elevated DNA damage.
KMT2C‐depleted cancer cells depend on PARP1/2 and are sensitive to PARP inhibitors.
EMBO Reports (2019) e46821
- Received July 27, 2018.
- Revision received December 17, 2018.
- Accepted December 19, 2018.
- © 2019 The Authors
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