Role of Arginine Methyltransferase in Disease - Desklib

Protein arginine methyltransferase is an enzyme that catalyses the methyl transfer to the arginine residue in protein which causes changes in biological phenomena. This essay discusses the role of protein arginine methyltransferase in various diseases such as cancer, pulmonary disorders, and more. Desklib provides study material with solved assignments, essays, and dissertations.

ROLE OF ARGININE
METHYLTRANSFERASE
IN DISEASE

Contents
INTRODUCTION...........................................................................................................................1
MAIN BODY...................................................................................................................................1
CONCLUSION ...............................................................................................................................7
REFERENCES................................................................................................................................8

INTRODUCTION
Protein arginine methyl transferase is the that is PRMT is an enzyme which is use to
catalyse the methyl transfer to the arginine residue in protein which cause changes in number of
biological phenomena like as signal transduction, chromatin regulation and RNA regulation. It
methylate several cytoplasmic and nuclear substrate and play a vital roles in different biological
phenomenon which include cell cycle progression, RNA processing, DNA damage repair and
Cell death (Yuan, and Nie, 2021). It is one of the one of the regulating enzymes which involves
in remodelling of chromatin via post translation modification of histone protein, therefore it is
known as epigenetic modulators. There are some abnormality of protein arginine methyl
transferase related to number of pathological situations like Cancer, Pulmonary fibrosis,
Pulmonary hypertension, Asthma, Chronic Obstructive pulmonary disorder and so on (Zhang,
and et. al., 2018). Some potent and selective inhibitors of Protein arginine methyl transferase are
vital because it can be used as biochemical tools to assist to acknowledge the operations of
PMRT in oncogenic and epigenetics and also it is a effective therapeutics targeting protein
methyl transferase arginine overexpression within different diseases (Adamopoulos, and et. al.,
2019). Protein arginine methylation is quickly growing area of biomedical research which holds
large promise to extend our acknowledge of pathological process and developmental process. In
this essay, role of protein arginine methyl transferase in various disease such as cancer, different
pulmonary disorder and many more like this will be going to discuss (Zhou, and et. al., 2022).
MAIN BODY
In mammalian genomes, there are nine protein arginine methyl transferase are encoded.
The protein arginine methyl transferase catalyses the 3 kinds of arginine methylation. Mono
methylation is consider as an intermediate in the synthesis of dimethylated arginine. Protein
arginine methyl transferase 5 is the primary enzyme accountable for symmetric dimethylation
and Protein arginine methyl transferase 1 is the primary enzyme accountable for asymmetric
dimethylation (Xu, and Richard, 2021). There are several role of protein methyl transferase
enzyme in Cancer, Immunology or inflammation and Infectious disease. PRMT6 that is protein
arginine methyl transferase 6 is consider as the member of the forty five – RTM enzyme family.
Protein arginine methyl transferase 6 is founded in the nucleus and may produce asymmetric and
mono, dimethyl Omega-N(G)- arginine derivatives on histones protein keeping a GAR motif.
1

Protein arginine methyl transferase 6 is the single RMT consider to methylation for the H3R2
mark (Beacon, Xu, and Davie, 2020). More expression of protein arginine methyl transferase 6
has been recorded in various kinds of cancer involving prostrate, lung and melanoma. Protein
arginine methyl transferase 6's small molecule inhibitors have some usefulness in contrast to
these cancer types. By the help of screening of its internal compound assemble in contrast to
protein methyl transferase 6, protein methyl transferase 8 and protein methyl transferase 6
Epizyme recognised aryl pyrazoles containing diamine side chains like keeping inhibitory
activity. Protein arginine methyl transferase 8's ternary crystal structure, S- adenosyl
homocysteine that is SAH and protein arginine 6 was produced (Che, and et. al., 2021).
The diamine side chain part of the compound captures the putative substrate site. The final
nitrogen atoms comes by close to the sulphur atom of S- adenosyl homocysteine and creates
number of water mediated hydrogen bond interaction to Glu164 and Trp156 and direct hydrogen
bonds to Glu 155. Protein arginine methyl transferases play a crucial roles in methylation
process. In which, PRMT 5 is the main type II arginine methyl transferase which catalyses the
transfer of 2 methyl groups proportionally to the residue of arginine of either non histone protein
2
Illustration 1: role of arginine methyl transferase
Sources:https://www.sciencedirect.com/science/article/pii/
S1574789114002646

and histone proteins. In the present day, enhancing proof has represented that protein arginine
methyl transferase, as an oncogene, shows an essential regulatory role in the disease progression
of number of human cancers through stimulating the invasion, migration and proliferation of the
cancers cell in human (Sengupta, and et. al., 2020). Protein arginine methyl transferase 5 is very
expressed in number of malignant tumour and takes part in essential role in the development and
occurrence of tumour, which proposes that protein arginine methyl transferase 5 can become a
effective therapeutic target or biomarker of cancer. Epigenetics is the phenomena of altering the
patterns of gene expression with mechanisms which do not consist the genetic coding and DNA
sequence. It is characterised through reversibility and heritability. The mechanisms of protein
arginine methyl transferase's action in methylations of protein involve post-transcriptional
regulation, alternative splicing, cell differentiation, cell proliferation, cell apoptosis, RNA
processing and Thermogenesis (Glenn, and et. al., 2018). Protein arginine methyl transferase 5 is
the essential type II arginine methyl transferase which catalyses the transfer of 2 methyl group
proportionally to the residue of arginine of either non-histone or histone proteins. It functions
through binding to the number of molecules in both the nucleus and the cytoplasm. Since
protein arginine methyl transferase is an epigenetic enzyme, it involves in more number of
physiological processes, together with ribosome biogenesis and transcriptional regulation
(Owens, and et. al., 2022). In addition, protein arginine methyl transferase can serve like an
oncogene and its more expression takes part in a different types of cancers as like as lung cancer,
oropharyngeal squamous cell carcinoma (OPSCC), human hepatocellular cancer, breast cancer
and so on. Protein arginine methyl transferase 5 is together with cancer cell proliferation, cell
invasion, migration and cell differentiation. According to the study conducted on mice models it
was founded that protein arginine methyl transferase restricted the transcription of the MIR-99
gene family through symmetrical dimethylation of histone protein named H4R3 (Guo,and et. al.,
2022). which stimulated the FGFR3 that is fibroblast growth factor receptor 3 expression and
apart from this activated AKT and ERK1/2, directing to to the metastasis and cell growth in the
lung cancer. In addition to this, protein arginine methyl transferase affects the EMT that is
epithelial to mesenchymal transition and it is regularly more expressed at the time of progression
of oral squamous cell carcinoma (OSCC) and oncogenesis, which provide validation that protein
arginine methyl transferase take part in the process of cell invasion. More interestingly, the role
and subcellular localization of protein arginine methyl transferase changes with the type of
3

tumour. In number of tumours target substrates and the localisation of protein arginine methyl
transferase in all cell chamber can be significantly contrasting (Okuno, and et. al., 2019).
According to the number of studies done in recent years it is suggested that knocking down the
protein arginine methyl transferase could restrict the process of growth of the tumour cells and
enhance the improvement process to prognosis of cancer patients, it implies that protein arginine
methyl transferase can be a novel and promising therapeutic goal for the treatment of various
tumours. Cancer is the a very impactful public health issue and it is one of the leading reason of
death globally (Hong, and et. al., 2022). Like number of patient of cancer are diagnosed at late
stages therefore conventional therapies shows very limited effects and the life live time period of
cancer patient becomes too poor. Early distant metastasis and chemotherapy resistance is the
chief challenges in the treatment of tumour cell. So, there is a great requirement for people to
interpret the molecular mechanism and find novel molecular markers to estimate prognosis more
correctly, in addition to this predict susceptible target organs to impactful therapies. Protein
arginine methyl transferase plays a important roles in lung cancer (Jan, and et. al., 2021). As per
the studies of latest research protein arginine methyl transferase was more strongly
immunostained in the samples of tumour however it was not present from samples of benign
lung tissue extracted from the patients of lung cancer. A very same study represented that level
of protein arginine mRNA was 6.13 fold more higher in NSCLC that is non small cell lung
cancer tissue than that in same non neoplastic pulmonary parenchyma. There are very high level
of protein arginine methyl transferase and its mediated proportional methylation of H4 histone at
3 arginine that is H4R3me2Ss, were found in ADC means lung adenocarcinoma and SQC that is
lung squamous cell carcinoma, but it is not found in bronchial epithelial cell lines and non-
neoplastic pulmonary alveolar (Nibona, and et. al., 2021). More number of protein arginine
methyl transferase in in cytoplasm of human was associated with very higher grade of cancer in
both pulmonary neuroendocrine tumours and non small cell lung cancer (NSCLC). According to
the another report it is revealed that protein arginine methyl transferase cytoplasmic expression
was often seen in high level subtypes of cancer however nuclear expression of protein arginine
methyl transferase was often observed in very low grade sub types of cancer among more
number of cases related to adenocarcinoma. The relationship between prognosis and protein
arginine methyl transferase expression has also been evaluated and the outcomes expressed that
upregulated protein arginine methyl transferase was very closely associated to lymphatic
4

metastasis, clinical stages and poor survival in the patients of lung cancer (Jiang,and et. al.,
2020). They cytoplasmic expression of protein arginine methyl transferase was closely related to
a bad prognosis. Apart from this multivariate analysis represented that protein arginine methyl
transferase level was an independent bad prognostic elements of non small cell lung cancer.
However the accurate role of protein arginine methyl transferase in human's lung cancer and the
followed mechanism is not fully cleared but its potential effects in human lung cancer is clearly
defined in both vivo and vitro condition (Liu, and et. al., 2020). Silencing protein arginine
methyl transferase 5 with protein arginine methyl transferase 5 shRNA impact fully restricted the
growth of cells of A594 and diminished the growth of A594 xenograft of lungs. In addition to
this, silencing protein arginine methyl transferase expression also lowered the levels of FGFR3
(fibroblast growth factor receptor 3), representing that protein arginine methyl transferase
regulated the growth of cell by the regulation of fibroblast growth factor receptor 3 expression
(Meng, and et. al., 2022). By the help of western blot evaluation represented that higher level of
cytoplasmic protein arginine methyl transferase was correlated to lower level of E-cadherin a
standard criterion of EMT showing that protein argenin methyl transferase took part in the EMT
process and associated with histologic grades of lung adenocarcinoma. Through restricting the
expressions of miR-99 family transcription factor via H4 histone at 3 arginine (H4R3me2s) in
liked promoter regions, protein agrginine methyl transferase regulated the expression of FGFR3
and regulated the growth of lung cancer and increase the speed of metastasis. By knocking down
the protein arginine methyl transferase impact fully restricted the growth of cell, growth of lung
cancer xenograft and colony formation of lung tumour (Mirza-Aghazadeh-Attari, and et. al.,
2019). WD repeat domain 77 and Protein arginine methyl transferase ( WD77, also considered as
p44, MEP50 and WD45) enhanced the growth by improving growth factors expression and
EGFR ( epidermal growth factor receptor), While lowering the expression of growth suppressors
leucine proline-enriched proteoglycan and B-cell translocation gene. Through interacting with
protein arginine methyl transferase, SHARPIN ( Shank-associated RH domain interacting
protein) plays a crucial role in mediating specific H3 arginine methylation, & in turns provokes
progression and invasion of lung cancer-cell. Therefore these outcomes pointed out that protein
arginine methyl transferase enzyme may be a useful prognostic, diagnostic and therapeutic
targets of cancer associated with lungs. Protein arginine methyl transferase play a very
significant role in breast cancer (Nath, and Kashfi, 2020). It's expression levels were vitally
5

upregulated in the case of breast cancer tissue with respect to the matched normal tissue.
Upregulated protein arginine methyl transferase expression was also recognised in the breast
cancer cell lines. Removal of protein arginine methyl transferase enzyme decreased the breast
cancer cell growth, cell proliferation, cell invasion, cell migration, and the cell cycle progression.
The interrelation evaluation displayed that more expression of protein arginine methyl
transferase was positively connected with big size of tumour, LNM (lymph nodes metastasis),
more advanced clinical stage, leading to bad prognosis, involving lowered OS or RFS (relapse
free survival) and inhibition of effects of drugs (Liu, and et. al., 2021). According to these
studies and findings, it is found that protein arginine methyl transferase could be self-reliant
prognostic biomarker for breast cancer. Therefore, aiming the protein arginine methyl transferase
might be the best plan for the treatment of breast cancer cell in human body. Functional analysis
displayed that silencing protein arginine methyl transferase effectively restricted the progression
of breast cancer cells. Apart from this, protein arginine methyl transferase controlled self renewal
and function of breast cancer stem cells via FOXP1 (Forkhead box protein P1) expression and
histone methylation (Liu, and et. al., 2021). Breast cancer stem cells are recognised through slow
pace of cell division, high capacity for Drug resistance and DNA repair and high expression of
efflux pump of drugs. As for example, protein arginine methyl transferase controlled the
expression heights of a panel of stem-ness related proteins, consisting KLF4,C-MYC and
OCT4/A in cancer associated with breast through affected the Doxorubicin resistance and
governing cell stemness of breast cancer. In addition, protein arginine methyl transferase enzyme
took part in cells apoptosis of BC MDA-MB-231 via the PARP which regulating through Bcl-2/
capsase 3/ poly (ADP-ribose) polymerase pathway (Neganova, and et. al., 2022). Protein
arginine methyl transferase nuclear expression was regulated through tumour necrosis factor
which is associated with 4 (TRAF4) mediated NF-KB ( nuclear factor- KB signalling route
activation in MCF-7 and BC MDA-MB-231 cells, guiding to proliferation of cell (Conery,
Rocnik, and Trojer, 2022). According to the above discussion, it was analysed that the breast
cancer patients with more protein arginine methyl transferase expression shown enhanced DDFS
(distant disease free survival) and DFS (disease free survival). Likewise, from the another
discussion it has been displayed that more nuclear protein arginine methyl transferase
representation was together with longer DFS and OS in breast cancer patients. CAPG that is
macrophages capping protein expression was enhanced in breast cancer tissue and increased
6

metastasis of cell cancer (Inoue, and et. al., 2022). The fundamental mechanism included
interaction of protein arginine methyl transferase with macrophage capping protein (CAPG) for
regulating transcription of STC-1 that is stanniocalcin 1, a gene which is related to metastasis.
Macrophage capping protein (CAPG) decreased interaction of STC- 1 gene promoter with
protein arginine methyl transferase and lowered histone H4R3 methylation dependent on PRMT
and thereafter, decrease methylation of CpG DNA, which cause enhancement in stanniocalcin 1
transcription (Thirupathi, and Chang, 2019).
Depletion of protein arginine methyl transferase increased the MDA-MB-231 HM cell invasion
and cell migration, pointing out that protein arginine methyl transferase takes part in an anti-
7
Illu
stration 2: role of arginine methyl transferase.
Sources: https://www.mdpi.com/2073-4409/10/1/124

metastatic role in breast cancer. Nuclear cancer suppressor LKB1 (liver kinase B1) associated
with protein arginine methyl transferase and its associate MEP50 (Methylosome protein 50) to
lower the activity of enzyme PRMT, and therefore, inhibits its cancer causing effect. Protein
arginine methyl transferase show a significant role in hepatocellular carcinoma also. In the recent
days, there are several evidences which represented that protein arginine methyl transferase
expression was stimulated in HCC ( human hepatocellular carcinoma) cell lines with respect to a
normal cell line of liver (Wang, and et. al., 2019). Equivalence evaluation shown that the
expression of protein arginine methyl transferase was positively interconnected with the size of
tumour, higher rate of recurrence and decreased overall survival to the patients of human
hepatocellular carcinoma. Multivariate cox regression evaluation shown that the stimulation of
protein arginine methyl transferase was an significant and independent precursor of prognosis in
human hepatocellular carcinoma after surgical abscission. Removal of protein arginine methyl
transferase potentially restricted proliferation of in vivo tumourigenesis and in vitro human
hepatocellular carcinoma (Guccione, and et. al., 2021). Consumption of protein arginine methyl
transferase enzyme guided to elimination of cell invasion through depletion of the expression of
MMP- 2 (matrix metalloproteinase – 2). Protein arginine methyl transferase enzyme enhanced
proliferation of human hepatocellular cancer cell trough inhibition of gene expression of BTG2
(B-cell translocation gene 2) by regulating the expression of cell cycle associated proteins like as
cyclin D1 with B-catenin and ERK pathway which directing to cell cycle arrest at the time of G1
phase. LINC01138 and protein arginine methyl transferase, behaving as drivers of oncogene,
enhanced cell invasion, cell proliferation and cell metastasis in human hepatocellular carcinoma
(Beketova, and et. al., 2022). Curiously, the mSREBP1a (mature form of sterol regulatory
element binding proteins 1a is the complex of methylated protein arginine methyl transferase
enzyme, promoted the hyper activation of the pathway of lipid biosynthesis, which is necessary
for development of cancer, directing to increased tumour growth and tumour cell proliferation
(Wang, and et. al., 2019). Eventually from the another study it is also confirmed that high
expression level of SET and PRMT5 domain consisting protein 8 were importantly associated
with bad total survival and recurrence time taken in patients with human hepatocellular cancer.
In conclusion, protein arginine takes part in a key role in modulating human hepatocellular
cancer cell growth and development of cancer cell. It can also serve as a new marker for
prognostic and effective therapeutic goals for human hepatocellular carcinoma. Protein arginine
8

cancer cell also keeps a specific role in gastrointestinal cancer, haematological malignancies,
glioblastoma, prostrate cancer , urothelial carcinoma of the bladder, head and neck cancer,
epithelial ovarian cancer and many more types of cancer occur in human bodies (Ghufran, Soni,
and Kanade, 2019).
CONCLUSION
From the above discussion it has been concluded that, there are nine protein arginine
methyl transferase are encoded in mammalian genomes. Protein arginine is one of the regulating
enzymes which takes par in remodelling of chromatin by post translation modification of histone
protein so, it is known as epigenetic modulators. Epigenetic introduce to the gene expression's
inheritable regulation without changing in the sequence of DNA molecules. It mainly consists
histone modification, DNA methylation, and remodelling of chromatin. DNA methylation is the
first known regulation mechanism of epigenetic which is related to the inhibition of gene. It take
part for vital role in embryonic development, cell differentiation and illness occurrence.
Abnormal modification of epigenetic may cause tumour and other different disease. Protein
arginine methyl transferase enzyme plays a vital role in methylation of protein and development
of different types of cancers. Due to the protein arginine methyl transferase enzyme several types
of disease occur like Cancer, Pulmonary fibrosis, Pulmonary hypertension, Asthma, Chronic
Obstructive pulmonary disorder and so on. In this essay majorly different types of human cancer
has been discussed in which arginine methyl transferase play a significant role.
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