Abstract
BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression. Significance: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5920-5929 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents. / Kanakkanthara, Arun; Kurmi, Kiran; Ekstrom, Thomas L.; Hou, Xiaonan; Purfeerst, Emma R.; Heinzen, Ethan P.; Correia, Cristina; Huntoon, Catherine J.; O'Brien, Daniel; Wahner Hendrickson, Andrea E.; Dowdy, Sean C.; Li, Hu; Oberg, Ann L.; Hitosugi, Taro; Kaufmann, Scott H.; Weroha, S. John; Karnitz, Larry M.
In: Cancer Research, Vol. 79, No. 23, 01.12.2019, p. 5920-5929.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents
AU - Kanakkanthara, Arun
AU - Kurmi, Kiran
AU - Ekstrom, Thomas L.
AU - Hou, Xiaonan
AU - Purfeerst, Emma R.
AU - Heinzen, Ethan P.
AU - Correia, Cristina
AU - Huntoon, Catherine J.
AU - O'Brien, Daniel
AU - Wahner Hendrickson, Andrea E.
AU - Dowdy, Sean C.
AU - Li, Hu
AU - Oberg, Ann L.
AU - Hitosugi, Taro
AU - Kaufmann, Scott H.
AU - Weroha, S. John
AU - Karnitz, Larry M.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression. Significance: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.
AB - BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression. Significance: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer.
UR - http://www.scopus.com/inward/record.url?scp=85076065139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076065139&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-1405
DO - 10.1158/0008-5472.CAN-19-1405
M3 - Article
C2 - 31619387
AN - SCOPUS:85076065139
VL - 79
SP - 5920
EP - 5929
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 23
ER -