BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents

Arun Kanakkanthara, Kiran Kurmi, Thomas L. Ekstrom, Xiaonan Hou, Emma R. Purfeerst, Ethan P. Heinzen, Cristina Correia, Catherine J. Huntoon, Daniel O'Brien, Andrea E. Wahner Hendrickson, Sean C. Dowdy, Hu Li, Ann L. Oberg, Taro Hitosugi, Scott H. Kaufmann, S. John Weroha, Larry M. Karnitz

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)5920-5929
Number of pages10
JournalCancer Research
Volume79
Issue number23
DOIs
StatePublished - Dec 1 2019

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Nicotinamide N-Methyltransferase
Ovarian Neoplasms
Up-Regulation
Recombinational DNA Repair
Homologous Recombination
Energy Metabolism
Respiration
Down-Regulation
Adenosine Triphosphate
Glucose
Mutation
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kanakkanthara, A., Kurmi, K., Ekstrom, T. L., Hou, X., Purfeerst, E. R., Heinzen, E. P., ... Karnitz, L. M. (2019). BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents. Cancer Research, 79(23), 5920-5929. https://doi.org/10.1158/0008-5472.CAN-19-1405

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 journalArticle

Kanakkanthara, A, Kurmi, K, Ekstrom, TL, Hou, X, Purfeerst, ER, Heinzen, EP, Correia, C, Huntoon, CJ, O'Brien, D, Wahner Hendrickson, AE, Dowdy, SC, Li, H, Oberg, AL, Hitosugi, T, Kaufmann, SH, Weroha, SJ & Karnitz, LM 2019, 'BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents', Cancer Research, vol. 79, no. 23, pp. 5920-5929. https://doi.org/10.1158/0008-5472.CAN-19-1405
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. / BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents. In: Cancer Research. 2019 ; Vol. 79, No. 23. pp. 5920-5929.
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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.",
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AU - Kanakkanthara, Arun

AU - Kurmi, Kiran

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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.

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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.

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