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 R.; Hendrickson, Andrea E. Wahner; Dowdy, Sean C.; Li, Hu; Oberg, Ann L.; Hitosugi, Taro; Kaufmann, Scott H.; Weroha, S. John; Karnitz, Larry M.

doi:10.1158/0008-5472.can-19-1405

Cited by 43 publications

(44 citation statements)

References 25 publications

(39 reference statements)

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“…More importantly, CDK12 LOF genomic alterations are associated with focal tandem duplications (FTDs) in ovarian cancer [64]. In addition, BRCA1 promoter hypermethylation or mutational inactivation of CDK12 can downregulate transcription of BRCA1, thereby disrupting HR DNA repair in ovarian cancer, and then leading to metabolic reprogramming of ovarian cancer cells [65]. A c.1047-2A>G splice site variant of the CDK12 gene was recently reported to be strongly associated with hereditary ovarian cancer [66].…”

Section: Cdk12 In Ovarian Cancermentioning

confidence: 99%

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Liang

et al. 2020

Cells

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Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12′s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

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Section: Cdk12 In Ovarian Cancermentioning

confidence: 99%

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Liang

et al. 2020

Cells

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“…To date, many researchers have found that anti-metabolic agents could promote the effective elimination of ovarian cancer cells. In addition, Kanakkanthara et al found that the repression of energy metabolism may be an alternative means of selectively targeting BRCA1-deficient OSCs, which is represented by BRCA1 loss and nicotinamide N-methyltransferase overexpression [5]. Zhang et al indicated that ACTL6A expression promotes the development and progression of ovarian cancer, especially in the glucose metabolism of cancer cells [6].…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of a prognostic index based on a metabolic-genomic landscape analysis of ovarian cancer

Zhang

Chen

et al. 2020

Bioscience Reports

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Purpose: Tumour metabolism has become a novel factor targeted by personalized cancer drugs. This research evaluated the prognostic significance of metabolism-related genes (MRGs) in ovarian serous cystadenocarcinoma (OSC). Methods: MRGs in 379 women surviving OSC were obtained using The Cancer Genome Atlas (TCGA) database. Then, several biomedical computational algorithms were employed to identify eight hub prognostic MRGs that were significantly relevant to OSC survival. These 8 genes have important clinical significance and prognostic value in OSC. Subsequently, a prognostic index was constructed. Drug sensitivity analysis was used to screen the key genes in eight MRGs. IHC staining confirmed the expression levels of key genes and their correlations with clinical parameters and prognosis for patients. Results: A total of 701 differentially expressed MRGs were confirmed in women with OSC by the TCGA database. The random walking with restart (RWR) algorithm and the univariate Cox and lasso regression analyses indicated a prognostic signature based on eight MRGs (i.e., ENPP1, FH, CYP2E1, HPGDS, ADCY9, NDUFA5, ADH1B and PYGB), which performed moderately well in prognostic predictions. Drug sensitivity analysis indicated that PYGB played a key role in the progression of OSC. Also, IHC staining confirmed that PYGB has a close correlation with clinical parameters and poor prognosis in OSC. Conclusion: The results of this study may help to establish a foundation for future research attempting to predict the prognosis of OSC patients and to characterize OSC metabolism.

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“…At the same time, the inhibition of electron transport chain complex I [273] and II [274] was show to suppress AML. In the same way, the impairment of mitochondrial respiration was reported to impede ovarian cancer progression [275], while the contemporary inhibition of glycolysis and OXPHOS was demonstrated to suppress breast cancer [276]. Similarly, the simultaneous abrogation of mitochondrial respiration and lactate export promotes cancer death in several in vitro cancer models [277].…”

Section: Metabolism and Cancer Therapymentioning

confidence: 95%

Metabolic Constrains Rule Metastasis Progression

Roda

Gambino

2020

Cells

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Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.

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BRCA1 Deficiency Upregulates NNMT, Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents

Cited by 43 publications

References 25 publications

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Identification and validation of a prognostic index based on a metabolic-genomic landscape analysis of ovarian cancer

Metabolic Constrains Rule Metastasis Progression

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