METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner

Dai, Yun-Zhang; Liu, Yong-da; Li, Jie; Chen, Meiting; Huang, Mei; Wang, Fang; Yang, Qingsong; Yuan, Ji‐hang; Sun, Shao-Guang

doi:10.1186/s11658-022-00342-8

Cited by 79 publications

(43 citation statements)

References 57 publications

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“…Moreover, the depletion of METTL16 inhibits gastric cancer (GC) and hepatocellular carcinoma (HCC) 51 . In accordance with this, high METTL16 expression has been linked with poor survival in the case of GC 52 and prognosis in the case of HCC 53 . It has been also shown that METTL16 binds to the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA 6 .…”

Section: Introductionsupporting

confidence: 60%

Novel RNA m⁶A methyltransferase METTL16 inhibitors

Selberg

Ivanova

Kotli

et al. 2023

Preprint

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The overexpression of RNA 6-N-methyladenosine (m6A) methyltransferase METTL16 has oncogenic role in the case of several cancer types, including leukemia, but efficient small-molecule inhibitors are not available. Initially identified by high-throughput virtual screening of the ZINC15 database in vivo subset, but then confirmed by measuring catalytic activity, two nanomolar-active METTL16 inhibitors, compounds 1 (IC50 = 25.82 ± 17.19 nM) and 2 (IC50 = 60.91 ± 2.75 nM) were found. The inhibitory activity of the compounds was measured using the m6A antibody-based ELISA assay. We also present the results on the effect of these inhibitors on the viability of promyeloblast HL-60 and lymphoblast CCRF-CEM leukemia cell lines. In unstressed growth conditions, both identified METTL16 inhibitors reduced the viability of HL-60 cells by up to 40%. The effect on the viability of CCRF-CEM cells was smaller with no dose dependency observed. In parallel, the level of the m6A as compared to unmodified adenosine in the HL-60 cell mRNAs was significantly reduced by the inhibitor 1. Collectively, we herein demonstrate novel METTL16 inhibitors that exert tumor cell-lineage-selective antiproliferative effects.

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Section: Introductionsupporting

confidence: 60%

Novel RNA m⁶A methyltransferase METTL16 inhibitors

Selberg

Ivanova

Kotli

et al. 2023

Preprint

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“…In gastric cancer, researchers found that METTL16 is highly expressed in cancer tissues, and METTL16-mediated m6A methylation promotes GC cell proliferation by enhancing cyclin D1 expression ( 35 ). The regulatory effects of METTL16 on malignant tumors ( 16 ) such as breast cancer ( 36 ) and liver cancer ( 37 ) have also been reported. However, in our study, we revealed for the first time that the novel m6A writer METTL16 was significantly decreased in PC cells and played a tumor suppressor role during human pancreatic carcinogenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway

Xie

Zheng

et al. 2023

Front. Oncol.

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BackgroundMany studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms and especially in the pathogenesis of malignant diseases. However, m6A research has mainly focused on methyltransferase activity mediated by METTL3, and few studies have focused on METTL16. The aim of this study was to investigate the mechanism of METTL16, which mediates m6A modification, and its role in pancreatic adenocarcinoma (PDAC) cell proliferation.MethodsClinicopathologic and survival data were retrospectively collected from 175 PDAC patients from multiple clinical centers to detect the expression of METTL16. CCK-8, cell cycle, EdU and xenograft mouse model experiments were used to evaluate the proliferation effect of METTL16. Potential downstream pathways and mechanisms were explored via RNA sequencing, m6A sequencing, and bioinformatic analyses. Regulatory mechanisms were studied through methyltransferase inhibition, RIP, MeRIP‒qPCR assays.ResultsWe found that METTL16 expression was markedly downregulated in PDAC, and multivariate Cox regression analyses revealed that METTL16 was a protective factor for PDAC patients. We also demonstrated that METTL16 overexpression inhibited PDAC cell proliferation. Furthermore, we identified a METTL16-p21 signaling axis, with downregulation of METTL16 resulting in inhibition of CDKN1A (p21). Additionally, METTL16 silencing and overexpression experiments highlighted m6A modification alterations in PDAC.ConclusionsMETTL16 plays a tumor-suppressive role and suppresses PDAC cell proliferation through the p21 pathway by mediating m6A modification. METTL16 may be a novel marker of PDAC carcinogenesis and target for the treatment of PDAC.

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“…Recent studies have demonstrated the central role of methyltransferase like proteins METTL1, METTL3, METTL6, METTL16, and METTL18 in regulating aberrant expression in human hepatocellular carcinoma tissues and pathogenesis and progression of HCC cells, such as cell survival, proliferation, metastasis, and invasion which in turns makes them novel biomarkers [11][12][13][14][15][16][17]. However, despite identifying a few multi-kinases or receptors targeting anti-cancer inhibitors, no multi-target drugs or inhibitors have been reported against HCC-associated METTL proteins [68].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, METTL16 is another identified m6A methyltransferase, which negatively correlated with decreased RAB11B-AS1 transcript expression in HCC tissues. Thus, the METTL16–RAB11B-AS1 regulatory axis and these above-mentioned methyltransferase family proteins become novel biomarkers and therapeutic targets for hepatocellular carcinoma [17].…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibitors Targeting Methyltransferase-Like (METTL) Proteins Against Hepatocellular Carcinoma: A Comprehensive Drug Repurposing Approach

Morshed¹,

Parvez

Akanda³

et al. 2023

Preprint

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An efficient and durable multi-targeted therapeutic drug against hepatocellular carcinoma (HCC) has recently been a growing concern for tackling the chemoresistance of approved anti-HCC drugs. Recent studies indicated that methyltransferase-like (METTL) proteins including METTL1, METTL3, METTL6, METTL16, and METTL18, have overexpressed and associated with the progression of HCC malignancy, and making them excellent biomarkers. Here, we present a series of bioinformatics study including novel compound repurposing approach, molecular docking, pharmacophore modeling, and molecular dynamic simulation, which revealed two first-in-class highly potent catalytic multi-target inhibitors (ZINC70666503 and ZINC13000658 with 87% and 82% drug scores, respectively) of methyltransferase-like proteins. Comparatively, these two inhibitors showed a notable binding affinity against studied METTL proteins. Furthermore, ADME and toxicity analysis suggested that these two commercially available compounds have good drug-likeliness properties with no potent toxic effects. Of note, the molecular dynamics study supported their conformational stability and high selectivity at the pocket of proteins' adenosine moiety of S-Adenosyl Methionine. However, this comprehensive analysis needs in vivo validation to facilitate multi-targeting therapeutic development against hepatocellular carcinoma.

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METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner

Cited by 79 publications

References 57 publications

Novel RNA m⁶A methyltransferase METTL16 inhibitors

Novel RNA m⁶A methyltransferase METTL16 inhibitors

The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway

Small Molecule Inhibitors Targeting Methyltransferase-Like (METTL) Proteins Against Hepatocellular Carcinoma: A Comprehensive Drug Repurposing Approach

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METTL16 promotes hepatocellular carcinoma progression through downregulating RAB11B-AS1 in an m6A-dependent manner

Cited by 79 publications

References 57 publications

Novel RNA m6A methyltransferase METTL16 inhibitors

Novel RNA m6A methyltransferase METTL16 inhibitors

The m6A methyltransferase METTL16 inhibits the proliferation of pancreatic adenocarcinoma cancer cells via the p21 signaling pathway

Small Molecule Inhibitors Targeting Methyltransferase-Like (METTL) Proteins Against Hepatocellular Carcinoma: A Comprehensive Drug Repurposing Approach

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Product

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Novel RNA m⁶A methyltransferase METTL16 inhibitors

Novel RNA m⁶A methyltransferase METTL16 inhibitors