Nicotinamide N-methyltransferase enhances chemoresistance in breast cancer through SIRT1 protein stabilization

Abstract

Background Nicotinamide N -methyltransferase (NNMT) is overexpressed in various human tumors and involved in the development and progression of several carcinomas. In breast cancer, NNMT was found to be overexpressed in several cell lines. However, the clinical relevance of NNMT in breast cancer is not yet clear. Methods NNMT expression in breast carcinoma was examined by immunohistochemistry, and then, its relationship with patient clinicopathological characteristics was analyzed. The effects of NNMT on chemoresistance in breast cancer cells were assessed by cell viability, colony formation, and apoptosis assay. The NNMT, SIRT1, p53, and acetyl-p53 proteins, which are involved in NNMT-related chemoresistance, were examined by Western blotting. The SIRT1 mRNA was examined by real-time PCR, and its activity was measured by using the SIRT1 deacetylase fluorometric reagent kit. Results NNMT expression was significantly higher (53.9%) in breast carcinoma than in paracancerous tissues (10.0%) and breast hyperplasia (13.3%). A high level of NNMT expression correlated with poor survival and chemotherapy response in breast cancer patients who received chemotherapy. Ectopic overexpression of NNMT significantly inhibited the apoptotic cell death and suppression of colony formation induced by adriamycin and paclitaxel. Mechanistic studies revealed that NNMT overexpression increased SIRT1 expression and promoted its activity. Either inhibition of SIRT1 by EX527 or knockdown of SIRT1 by siRNA could reverse NNMT-mediated resistance to adriamycin and paclitaxel, which suggests that SIRT1 plays a critical role in NNMT-related chemoresistance in breast cancer. Conclusions The results of this study demonstrate a novel correlation between the NNMT expression level and patient survival, suggesting that NNMT has the potential to become a new prognostic biomarker to predict the treatment outcomes of the clinical chemotherapy in breast cancer. Moreover, targeting NNMT or downstream SIRT1 may represent a new therapeutic approach to improve the efficacy of breast cancer chemotherapy. Electronic supplementary material The online version of this article (10.1186/s13058-019-1150-z) contains supplementary material, which is available to authorized users.

Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells

“…NNMT has been recently reported to participate in the development and progression of various carcinomas and regulate cancer metabolism [12]. In breast cancer, we have found that NNMT and its product 1MNA can inhibit the mitochondrion-mediated apoptosis through decreasing intracellular ROS, which enhances the resistance to chemotherapy by SIRT1 protein stabilization [11,15]. Considering that the NNMT gene was predicted to be an autophagy regulator by genome-wide analysis [21], we investigated the role of NNMT in the autophagy of breast cancer cells.…”

“…Therefore, NNMT participates in the intracellular methylation cycle, which affects the global methylation status and metabolome of cells [6]. In the past decade, NNMT was found to be highly expressed in many kinds of tumour [7][8][9][10][11] and was found to alter various cancer cell metabolism pathways to regulate the cellular stress response [12,13] and epigenetic state, which results in high expression of protumour genes [14]. In our previous study, we found that NNMT and its product 1MNA can decrease the mitochondria-mediated apoptosis by suppressing intracellular ROS in breast cancer cells [15].…”

Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells

“…Despite an inhibitory or synergistic suppressive effect observed in the cells, in vivo confirmative observations are missing. Concerning breast cancer, EX-527 has been implicated in chemoresistance in several studies when being combined with different drugs 39 - 41 .…”

Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples

“…Recently, it was reported that aggressive cancer cell lines have higher levels of 1-MNA because of increased NNMT activity 9 . This is supported by data showing NNMT is highly expressed in various cancers 8 , and inhibition of NNMT results in suppression of cancer progression [10][11][12][13][14][15][16] . Therefore, it is important to develop NNMT inhibitors to eradicate cancer propagation in the clinic.…”