Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression

Manning, Morenci; Jiang, Yuanyuan; Wang, Rui; Liu, Lanxin; Rode, Shomita; Bonahoom, Madison; Kim, Seongho; Yang, Zeng-Quan

doi:10.1080/15476286.2019.1708549

Cited by 34 publications

(33 citation statements)

References 122 publications

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“…FTSJ2 (also known as MRM2) is a mitochondrial rRNA methyltransferase [52]. Human FTSJ3, which likely catalyzes 2'-O-Me of both rRNA and internal sites of mRNA, is a potential regulator of breast cancer progression [53]. Furthermore, FTSJ3 catalyzes 2'-O-Me of HIV RNAs and leads to the inhibition of innate immune sensing and response [45].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

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Three coronaviruses (CoVs): severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently identified SARS-CoV-2 in December 2019, have caused deadly pneumonia in humans since the beginning of the 21st century. The SARS-CoV-2 causes coronavirus disease-19 (COVID-19) with influenza-like symptoms ranging from mild discomfort to severe lung injury and multi-organ failure, eventually leading to death. As of April 30, 2020, more than three million (3,175,207) COVID-19 cases were reported worldwide, and more than 220,000 (224,172) patients have died (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Thus, it will be of great benefit to identify and repurpose already well-characterized compounds and approved drugs for use in combating COVID-19. CoVs are positive-sense RNA viruses that replicate in the cytoplasm of infected cells. Replication and transcription of the CoV RNA genome are achieved by a complex RNA replication/transcription machinery, consisting of at least 16 viral nonstructural proteins (nsp). Previous studies demonstrated that nsp16 proteins of SARS-CoV-1 and MERS-CoV have methyltransferase (MTase) activities that catalyze methylation of the first transcribed nucleotide at the ribose 2’-O position (2’-O-Me). The 2’-O-Me of virus cap RNAs protects itself from degradation by 5′-3′ exoribonucleases, ensures efficient translation, and helps to prevent recognition by the host innate immune system. The importance of nsp16 2'-O-MTase activity for CoV infection and pathogenesis was previously documented by in vitro and in vivo studies. For SARS-CoV-1, the absence of nsp16 2′-O-MTase activity results in significant attenuation characterized by decreased viral replication, reduced weight loss, and limited breathing dysfunction in mice. In addition, nsp16 down-regulates the activities of innate immune sensing factors: retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 protein (MDA5). Thus, inhibition of nsp16 2’-O-MTase activities should restrain viral replication and enable recognition by the host innate immune system, making the nsp16-MTase a promising target for the identification of new anti-SARS-CoV-2 drugs. In the present study, we employed structural analysis, virtual screening, and systematic drug repurposing approaches to identify “approved” drugs which can act as promising inhibitors against nsp16 2′-O-MTase of SARS-CoV-2. We first performed comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs and defined the key residues for nsp16 2-O’-MTase functions. From the virtual screening against nsp16 2′-O-MTase of SARS-CoV-2, we provide a ranking of the predicted binding affinities of 1,380 top hit compounds corresponding to 967 “approved” drugs. Furthermore, we have calculated various structural parameters of our top-ranking drugs. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and clinically for COVID-19 treatment.

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Section: Discussionmentioning

confidence: 99%

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Jiang¹,

Liu²,

Manning³

et al. 2020

Preprint

Self Cite

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“…DNA hypomethylation has also been found to be associated with increased NSUN2 expression in breast cancer, and NSUN2 overexpression promoted cell proliferation, migration, and invasion while NSUN2 knockdown inhibited these processes in vitro and in vivo [ 97 ]. A more detailed pan-cancer analysis has determined that expression of several RNMTs, including NSUN2, had positive correlations between DNA copy number and mRNA expression and was associated with higher grade aggressive subtypes and poor prognosis in breast cancer patients [ 98 ]. While the initial studies of NSUN2 in breast cancer found no association with ER status or Ki67 [ 95 ], in contrast, the study by Yi et al found significant correlations with estrogen receptor, Ki-67, and the progesterone receptor [ 97 ].…”

Section: Known Roles For Nsun2 In Cancermentioning

confidence: 99%

“…Most recently, a pan-cancer analysis of RNMTs has shown that alterations to NSUN2 are common in lung cancer [ 98 ], although this was not followed up in more detail. In this regard, cBioPortal analysis [ 111 , 112 ] of the TCGA lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets indicates that alterations to NSUN2 were found in 37% and 44% of samples, respectively ( Figure 3 ).…”

Section: Known Roles For Nsun2 In Cancermentioning

confidence: 99%

The RNA Methyltransferase NSUN2 and Its Potential Roles in Cancer

Chellamuthu

Gray

2020

Cells

130

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5-methylcytosine is often associated as an epigenetic modifier in DNA. However, it is also found increasingly in a plethora of RNA species, predominantly transfer RNAs, but increasingly found in cytoplasmic and mitochondrial ribosomal RNAs, enhancer RNAs, and a number of long noncoding RNAs. Moreover, this modification can also be found in messenger RNAs and has led to an increasing appreciation that RNA methylation can functionally regulate gene expression and cellular activities. In mammalian cells, the addition of m5C to RNA cytosines is carried out by enzymes of the NOL1/NOP2/SUN domain (NSUN) family as well as the DNA methyltransferase homologue DNMT2. In this regard, NSUN2 is a critical RNA methyltransferase for adding m5C to mRNA. In this review, using non-small cell lung cancer and other cancers as primary examples, we discuss the recent developments in the known functions of this RNA methyltransferase and its potential critical role in cancer.

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“…The protein contains a putative RNA-methyltransferase domain (FtsJ) in the N-terminal region and two uncharacterized domains in the central (DUF3381) and C-terminal (Spb1_C) regions [95]. A recent study demonstrates a functional role of FTSJ3 in promoting BC growth and survival, therefore representing a novel putative target for anticancer treatment [96]. The essential gene RNA helicase A (DHX9) is a protein responsible to regulate transcription in an ATP-dependent manner and involved in chromatin remodeling identified by Tarallo et al [89].…”

Section: Interaction Proteomics As Tool For Estrogen Signaling Proteimentioning

confidence: 99%

“…The protein contains a putative RNA-methyltransferase domain (FtsJ) in the N-terminal region and two uncharacterized domains in the central (DUF3381) and Cterminal (Spb1_C) regions [95]. A recent study demonstrates a functional role of FTSJ3 in promoting BC growth and survival, therefore representing a novel putative target for anticancer treatment [96].…”

Section: Interaction Proteomics As Tool For Estrogen Signaling Proteimentioning

confidence: 99%

Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

Salvati

Gigantino

Nassa

et al. 2020

IJMS

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Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies.

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Pan-cancer analysis of RNA methyltransferases identifies FTSJ3 as a potential regulator of breast cancer progression

Cited by 34 publications

References 122 publications

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

Repurposing Therapeutics to Identify Novel Inhibitors Targeting 2'-O-Ribose Methyltransferase Nsp16 of SARS-CoV-2

The RNA Methyltransferase NSUN2 and Its Potential Roles in Cancer

Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

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