Deregulation of Nicotinamide N-Methyltransferase and Gap Junction Protein Alpha-1 Causes Metastasis in Adenoid Cystic Carcinoma

Ishibashi, Kana; Ishii, Kazuya; Sugiyama, Goro; Sumida, Tomoki; Sugiura, Tetsuro; Kamata, Y U; Seki, Kiyohiko; Fujinaga, Takahiro; Kumamaru, Wataru; Kobayashi, Yasuhiko; Hiyake, Naomi; Nakano, Hirofumi; Yamada, Tomohiro; Mori, Yoshihide

doi:10.21873/anticanres.12207

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…This observation is supported by single-cell gene expressing data, showing the highest NNMT expression levels in the ccRCC tumour compartment. Eckert et al and several other studies identified NNMT as a metastasis-associated gene, [54][55][56][57] possibly acting by inducing the expression of matrix-metalloproteinase 2 (MMP-2) 8 and maintaining dedifferentiated mesenchymal-like gene expression. 13,58 In agreement, we observed deregulated metastasis-associated genes in NNMT kd knockdown cells in our study, including MMP-13, laminin subunit gamma 2 (LAMC2) and alpha-1,6-mannosylglycoprotein 6-beta-Nacetylglucosaminyltransferase (MGAT5).…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma

Reustle

Menig

Leuthold

et al. 2022

Clinical & Translational Med

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Background The metabolic enzyme nicotinamide‐N‐methyltransferase (NNMT) is highly expressed in various cancer entities, suggesting tumour‐promoting functions. We systematically investigated NNMT expression and its metabolic interactions in clear cell renal cell carcinoma (ccRCC), a prominent RCC subtype with metabolic alterations, to elucidate its role as a drug target. Methods NNMT expression was assessed in primary ccRCC (n = 134), non‐tumour tissue and ccRCC‐derived metastases (n = 145) by microarray analysis and/or immunohistochemistry. Findings were validated in The Cancer Genome Atlas (kidney renal clear cell carcinoma [KIRC], n = 452) and by single‐cell analysis. Expression was correlated with clinicopathological data and survival. Metabolic alterations in NNMT‐depleted cells were assessed by nontargeted/targeted metabolomics and extracellular flux analysis. The NNMT inhibitor (NNMTi) alone and in combination with the inhibitor 2‐deoxy‐D‐glucose for glycolysis and BPTES (bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl‐sulfide) for glutamine metabolism was investigated in RCC cell lines (786‐O, A498) and in two 2D ccRCC‐derived primary cultures and three 3D ccRCC air–liquid interface models. Results NNMT protein was overexpressed in primary ccRCC (p = 1.32 × 10–16) and ccRCC‐derived metastases (p = 3.92 × 10–20), irrespective of metastatic location, versus non‐tumour tissue. Single‐cell data showed predominant NNMT expression in ccRCC and not in the tumour microenvironment. High NNMT expression in primary ccRCC correlated with worse survival in independent cohorts (primary RCC—hazard ratio [HR] = 4.3, 95% confidence interval [CI]: 1.5–12.4; KIRC—HR = 3.3, 95% CI: 2.0–5.4). NNMT depletion leads to intracellular glutamine accumulation, with negative effects on mitochondrial function and cell survival, while not affecting glycolysis or glutathione metabolism. At the gene level, NNMT‐depleted cells upregulate glycolysis, oxidative phosphorylation and apoptosis pathways. NNMTi alone or in combination with 2‐deoxy‐D‐glucose and BPTES resulted in inhibition of cell viability in ccRCC cell lines and primary tumour and metastasis‐derived models. In two out of three patient‐derived ccRCC air–liquid interface models, NNMTi treatment induced cytotoxicity. Conclusions Since efficient glutamine utilisation, which is essential for ccRCC tumours, depends on NNMT, small‐molecule NNMT inhibitors provide a novel therapeutic strategy for ccRCC and act as sensitizers for combination therapies.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma

Reustle

Menig

Leuthold

et al. 2022

Clinical & Translational Med

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“…Several studies that investigated the activity and the biological role of NNMT, found high NNMT mRNA and protein levels and high catalytic activity in different cancer cell lines, including LSCC cell lines [ 34 ], ESCC cell lines EC9706 and TE1 [ 13 ], and PTC cell line BHP 2-7 [ 39 ]. Moreover, NNMT upregulation from low tumorigenic to the highly metastatic AdCC cell lines was demonstrated [ 35 ]. These studies also explored the involvement of NNMT on modulating cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The microarray analysis demonstrated that NNMT expression was 2.0 times higher in ACCS-LN-GFP than in ACCS-metastatic-GFP cells (ACCS-M-GFP). Furthermore, the NNMT mRNA and NNMT protein levels of ACCS-M-GFP, and even more of ACCS-LN-GFP, were significantly higher compared to those in the ACCS-GFP cell line [ 35 ]. This data supports the critical role of NNMT in AdCC invasion and metastasis.…”

Section: Other Tumors Of Maxillo-facial Regionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

et al. 2021

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The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide N-methyltransferase (NNMT). However, its biological effects have not been completely disclosed and the role of NNMT in cancer cell metabolism remains unclear. Therefore, this comprehensive review aims to evaluate the available literature regarding the biological, diagnostic, and prognostic role of NNMT in HNT. NNMT was shown to be significantly overexpressed in all of the evaluated HNT types. Moreover, its upregulation has been correlated with cancer cell migration and adverse clinical outcomes, such as high-pathological stage, lymph node metastasis, and locoregional recurrences. However, in oral squamous cell carcinoma (OSCC) these associations are still debated, and several studies have failed to demonstrate the prognostic significance of NNMT. The shRNA-mediated gene silencing efficiently suppressed the NNMT gene expression and exhibited a clear inhibitory effect on cell proliferation, promoting the expression of apoptosis-related proteins and modulating the cell cycle. NNMT could represent a new molecular biomarker and a new target of molecular-based therapy, although further studies on larger patient cohorts are needed to explore its biological role in HNT.

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“…In some instances, it has been observed that CSCs have low expression of connexin genes and exhibit low GJIC (e.g., [123][124][125]; see also reviews on the topic [125,126]). This is supported by some observations in CSCs or CSC-like cells from glioma [127,128], liver cancer [129,130], lung cancer [131,132], triple-negative breast cancer [76], and adenoid cystic carcinoma [133]. However, other studies have shown the presence of GJIC in glioblastoma [33,134], gastric cancer [135], lung cancer [136], and breast cancer [137,138].…”

Section: Cancer Stem Cellsmentioning

confidence: 63%

Connexins in Cancer: Jekyll or Hyde?

2020

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The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.

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Deregulation of Nicotinamide N-Methyltransferase and Gap Junction Protein Alpha-1 Causes Metastasis in Adenoid Cystic Carcinoma

Abstract: NNMT is a potential biomarker of AdCC.

Cited by 4 publications

References 31 publications

Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma

Nicotinamide‐N‐methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma

Nicotinamide N-Methyltransferase in Head and Neck Tumors: A Comprehensive Review

Connexins in Cancer: Jekyll or Hyde?

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