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Article: An epi(c)genetic war: Pathogens, cancer and human genome.

Rajagopalan, Deepa / Jha, Sudhakar

Biochimica et biophysica acta. Reviews on cancer

2018 Volume 1869, Issue 2, Page(s) 333–345

Abstract: Cancer is characterized by inter- and intra-tumor heterogeneity and this is also observed in the context of cancers caused by pathogens. Nearly 20% of all cancers are attributable to pathogenic organisms. Pathogenic infections result in deregulation of ... ...

Abstract	Cancer is characterized by inter- and intra-tumor heterogeneity and this is also observed in the context of cancers caused by pathogens. Nearly 20% of all cancers are attributable to pathogenic organisms. Pathogenic infections result in deregulation of gene expression both by genetic and epigenetic mechanisms, thereby causing malignant transformation. Another characteristic of pathogen-induced cancers is the occurrence of chronic inflammation due to activation of the innate and adaptive arms of the immune system. This review focuses on the epigenetic changes induced by oncoviruses, parasites, cancer-causing bacteria and 'endogenous pathogens' to trigger host cell proliferation indefinitely as well as the inflammation associated with pathogen-induced cancers. The opportunity of targeting components of both pathogen and host epigenetic machinery to limit tumor progression is also discussed.
MeSH term(s)	Animals ; Cell Transformation, Viral/genetics ; Epigenesis, Genetic ; Gene Expression Regulation, Bacterial ; Gene Expression Regulation, Neoplastic ; Gene Expression Regulation, Viral ; Genetic Heterogeneity ; Genome, Human ; Host-Pathogen Interactions ; Humans ; Neoplasms/genetics ; Neoplasms/microbiology ; Neoplasms/parasitology ; Neoplasms/virology
Language	English
Publishing date	2018-04-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0304-419X ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0304-419X ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbcan.2018.04.003
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Article: The oncogenic E3 ligase TRIP12 suppresses epithelial-mesenchymal transition (EMT) and mesenchymal traits through ZEB1/2.

Lee, Kwok Kin / Rajagopalan, Deepa / Bhatia, Shreshtha Sailesh / Tirado-Magallanes, Roberto / Chng, Wee Joo / Jha, Sudhakar

Cell death discovery

2021 Volume 7, Issue 1, Page(s) 95

Abstract: Thyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. ... ...

Abstract	Thyroid hormone receptor interactor 12 (TRIP12) is an E3 ligase most notably involved in the proteolytic degradation of the tumor suppressor p14ARF. Through this process, it is proposed that TRIP12 plays an oncogenic role in tumor initiation and growth. However, its role in other cancer processes is unknown. In this study, using publicly available cancer patient datasets, we found TRIP12 to be associated with distant metastasis-free survival in breast cancer, suggesting an inhibitory role in metastasis. Following TRIP12 depletion, an epithelial-mesenchymal transition (EMT) shift occurred with concomitant changes in EMT cell adhesion markers identified through RNA-seq. In line with EMT changes, TRIP12-depleted cells gained mesenchymal traits such as loss of cell polarity, dislodgement from bulk cells at a higher frequency, and increased cellular motility. Furthermore, ectopic TRIP12 expression sensitized cells to anoikis. Mechanistically, TRIP12 suppresses EMT through inhibiting ZEB1/2 gene expression, and ZEB1/2 depletion rescues EMT markers and mesenchymal behavior. Overall, our study delineates TRIP12's role in inhibition of EMT and implies a potential suppressive role in breast cancer metastasis.
Language	English
Publishing date	2021-05-07
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-021-00479-z
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Article ; Online: Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity.

Nature communications

2024 Volume 15, Issue 1, Page(s) 567

Abstract: Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single ... ...

Abstract	Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy.
MeSH term(s)	Humans ; Interferon Type I ; COVID-19 ; Cross-Sectional Studies ; SARS-CoV-2 ; Up-Regulation
Chemical Substances	Interferon Type I
Language	English
Publishing date	2024-01-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44524-0
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Article ; Online: Systematic immune cell dysregulation and molecular subtypes revealed by single-cell RNA-seq of subjects with type 1 diabetes.

Honardoost, Mohammad Amin / Adinatha, Andreas / Schmidt, Florian / Ranjan, Bobby / Ghaeidamini, Maryam / Arul Rayan, Nirmala / Gek Liang Lim, Michelle / Joanito, Ignasius / Xiao Xuan Lin, Quy / Rajagopalan, Deepa / Qi Mok, Shi / Hwang, You Yi / Larbi, Anis / Khor, Chiea Chuen / Foo, Roger / Boehm, Bernhard Otto / Prabhakar, Shyam

Genome medicine

2024 Volume 16, Issue 1, Page(s) 45

Abstract: Background: Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting : Methods: In this cross-sectional analysis, we generated a single-cell ... ...

Abstract	Background: Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting Methods: In this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (stage 3) cases and 31 matched controls. Results: We surprisingly detected profound alterations in circulatory immune cells (1784 dysregulated genes in 13 immune cell types), far exceeding the count in the comparator systemic autoimmune disease SLE. Genes upregulated in T1DM were involved in WNT signaling, interferon signaling and migration of T/NK cells, antigen presentation by B cells, and monocyte activation. A significant fraction of these differentially expressed genes were also altered in T1DM pancreatic islets. We used the single-cell data to construct a T1DM metagene z-score (TMZ score) that distinguished cases and controls and classified patients into molecular subtypes. This score correlated with known prognostic immune markers of T1DM, as well as with drug response in clinical trials. Conclusions: Our study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes, and has the potential to guide non-invasive test development and patient stratification.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 1/genetics ; Leukocytes, Mononuclear/metabolism ; Cross-Sectional Studies ; Single-Cell Gene Expression Analysis ; Autoimmune Diseases
Language	English
Publishing date	2024-03-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-024-01300-z
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Article: The large protein ‘L’ of Peste-des-petits-ruminants virus exhibits RNA triphosphatase activity, the first enzyme in mRNA capping pathway

Ansari, Mohammad Yunus / Singh, Piyush Kumar / Rajagopalan, Deepa / Shanmugam, Purnima / Bellur, Asutosh / Shaila, Melkote Subbarao

Virus genes. 2019 Feb., v. 55, no. 1

2019

Abstract: Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus—Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related ...

Abstract	Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus—Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related to Rinderpest virus (RPV). The large protein ‘L’ of the members of this genus is a multifunctional catalytic protein, which transcribes and replicates the viral genomic RNA as well as possesses mRNA capping, methylation and polyadenylation activities; however, the detailed mechanism of mRNA capping by PPRV L protein has not been studied. We have found earlier that the L protein of RPV has RNA triphosphatase (RTPase), guanylyltransferase (GTase) and methyltransferase activities, and unlike vesicular stomatitis virus (VSV), follows the conventional pathway of mRNA capping. In the present work, using a 5′-end labelled viral RNA as substrate, we demonstrate that PPRV L protein has RTPase activity when present in the ribonucleoprotein complex of purified virus as well as recombinant L–P complex expressed in insect cells. Further, a minimal domain in the C-terminal region (aa1640–1840) of the L protein has been expressed in E. coli and shown to exhibit RTPase activity. The RTPase activity of PPRV L protein is metal-dependent and functions with a divalent cation, either magnesium or manganese. In addition, RTPase associated nucleotide triphosphatase activity (NTPase) of PPRV L protein is also demonstrated. This work provides the first detailed study of RTPase activity and identifies the RTPase domain of PPRV L protein.
Keywords	manganese ; peste des petits ruminants ; messenger RNA ; methyltransferases ; Small ruminant morbillivirus ; methylation ; Rinderpest morbillivirus ; ribonucleoproteins ; sheep ; cations ; magnesium ; transcription (genetics) ; viruses ; genomics ; Vesiculovirus ; enzyme activity ; goat diseases ; insects ; Escherichia coli
Language	English
Dates of publication	2019-02
Size	p. 68-75.
Publishing place	Springer US
Document type	Article
Note	2019-12-06
ZDB-ID	639496-6
ISSN	1572-994X ; 0920-8569
ISSN (online)	1572-994X
ISSN	0920-8569
DOI	10.1007/s11262-018-1617-5
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Article ; Online: The large protein 'L' of Peste-des-petits-ruminants virus exhibits RNA triphosphatase activity, the first enzyme in mRNA capping pathway.

Ansari, Mohammad Yunus / Singh, Piyush Kumar / Rajagopalan, Deepa / Shanmugam, Purnima / Bellur, Asutosh / Shaila, Melkote Subbarao

Virus genes

2018 Volume 55, Issue 1, Page(s) 68–75

Abstract: Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus-Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related ...

Abstract	Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus-Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related to Rinderpest virus (RPV). The large protein 'L' of the members of this genus is a multifunctional catalytic protein, which transcribes and replicates the viral genomic RNA as well as possesses mRNA capping, methylation and polyadenylation activities; however, the detailed mechanism of mRNA capping by PPRV L protein has not been studied. We have found earlier that the L protein of RPV has RNA triphosphatase (RTPase), guanylyltransferase (GTase) and methyltransferase activities, and unlike vesicular stomatitis virus (VSV), follows the conventional pathway of mRNA capping. In the present work, using a 5'-end labelled viral RNA as substrate, we demonstrate that PPRV L protein has RTPase activity when present in the ribonucleoprotein complex of purified virus as well as recombinant L-P complex expressed in insect cells. Further, a minimal domain in the C-terminal region (aa1640-1840) of the L protein has been expressed in E. coli and shown to exhibit RTPase activity. The RTPase activity of PPRV L protein is metal-dependent and functions with a divalent cation, either magnesium or manganese. In addition, RTPase associated nucleotide triphosphatase activity (NTPase) of PPRV L protein is also demonstrated. This work provides the first detailed study of RTPase activity and identifies the RTPase domain of PPRV L protein.
MeSH term(s)	Acid Anhydride Hydrolases/metabolism ; Animals ; Baculoviridae/genetics ; Chlorocebus aethiops ; Cloning, Molecular ; Enzyme Activation ; Gene Expression ; Genetic Vectors/genetics ; Peste-des-Petits-Ruminants/virology ; Peste-des-petits-ruminants virus/physiology ; RNA Caps/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Vero Cells ; Viral Proteins/metabolism
Chemical Substances	RNA Caps ; RNA, Messenger ; Viral Proteins ; Acid Anhydride Hydrolases (EC 3.6.-) ; RNA triphosphatase (EC 3.6.1.-)
Language	English
Publishing date	2018-12-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	639496-6
ISSN	1572-994X ; 0920-8569
ISSN (online)	1572-994X
ISSN	0920-8569
DOI	10.1007/s11262-018-1617-5
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Article ; Online: Human Nasal Epithelial Cells Sustain Persistent SARS-CoV-2 Infection

Gamage, Akshamal M / Tan, Kai Sen / Chan, Wharton O Y / Lew, Zhe Zhang Ryan / Liu, Jing / Tan, Chee Wah / Rajagopalan, Deepa / Lin, Quy Xiao Xuan / Tan, Le Min / Venkatesh, Prasanna Nori / Ong, Yew Kwang / Thong, Mark / Lin, Raymond Tzer Pin / Prabhakar, Shyam / Wang, De Yun / Wang, Lin-Fa

mBio

2022 Volume 13, Issue 1, Page(s) e0343621

Abstract: The dynamics of SARS-CoV-2 infection in COVID-19 patients are highly variable, with a subset of patients demonstrating prolonged virus shedding, which poses a significant challenge for disease management and transmission control. In this study, the long- ... ...

Abstract	The dynamics of SARS-CoV-2 infection in COVID-19 patients are highly variable, with a subset of patients demonstrating prolonged virus shedding, which poses a significant challenge for disease management and transmission control. In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Post-Acute COVID-19 Syndrome ; Epithelial Cells ; Antiviral Agents
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2022-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.03436-21
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Article ; Online: Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer.

Thng, Dexter Kai Hao / Hooi, Lissa / Toh, Clarissa Chin Min / Lim, Jhin Jieh / Rajagopalan, Deepa / Syariff, Imran Qamar Charles / Tan, Zher Min / Rashid, Masturah Bte Mohd Abdul / Zhou, Lei / Kow, Alfred Wei Chieh / Bonney, Glenn Kunnath / Goh, Brian Kim Poh / Kam, Juinn Huar / Jha, Sudhakar / Dan, Yock Young / Chow, Pierce Kah Hoe / Toh, Tan Boon / Chow, Edward Kai-Hua

Molecular oncology

2023 Volume 17, Issue 11, Page(s) 2275–2294

Abstract: Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We ... ...

Abstract	Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Epigenesis, Genetic ; Histocompatibility Antigens/genetics ; Histocompatibility Antigens/metabolism ; Histocompatibility Antigens/therapeutic use ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Methylation
Chemical Substances	EHMT2 protein, human (EC 2.1.1.43) ; Histocompatibility Antigens ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; CDK9 protein, human (EC 2.7.11.22)
Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13417
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Article: The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning

Gherasim, Carmen / Hannibal, Luciana / Rajagopalan, Deepa / Jacobsen, Donald W / Banerjee, Ruma

Biochimie. 2013 May, v. 95, no. 5

2013

Abstract: Mutations in cobalamin or B₁₂ trafficking genes needed for cofactor assimilation and targeting lead to inborn errors of cobalamin metabolism. The gene corresponding to one of these loci, cblD, affects both the mitochondrial and cytoplasmic pathways for B₁ ...

Abstract	Mutations in cobalamin or B₁₂ trafficking genes needed for cofactor assimilation and targeting lead to inborn errors of cobalamin metabolism. The gene corresponding to one of these loci, cblD, affects both the mitochondrial and cytoplasmic pathways for B₁₂ processing. We have demonstrated that fibroblast cell lines from patients with mutations in CblD, can dealkylate exogenously supplied methylcobalamin (MeCbl), an activity catalyzed by the CblC protein, but show imbalanced intracellular partitioning of the cofactor into the MeCbl and 5′-deoxyadenosylcobalamin (AdoCbl) pools. These results confirm that CblD functions downstream of CblC in the cofactor assimilation pathway and that it plays an important role in controlling the traffic of the cofactor between the competing cytoplasmic and mitochondrial routes for MeCbl and AdoCbl synthesis, respectively. In this study, we report the interaction of CblC with four CblD protein variants with variable N-terminal start sites. We demonstrate that a complex between CblC and CblD can be isolated particularly under conditions that permit dealkylation of alkylcobalamin by CblC or in the presence of the corresponding dealkylated and oxidized product, hydroxocobalamin (HOCbl). A weak CblC·CblD complex is also seen in the presence of cyanocobalamin. Formation of the CblC·CblD complex is observed with all four CblD variants tested suggesting that the N-terminal 115 residues missing in the shortest variant are not essential for this interaction. Furthermore, limited proteolysis of the CblD variants indicates the presence of a stable C-terminal domain spanning residues ∼116–296. Our results are consistent with an adapter function for CblD, which in complex with CblC·HOCbl, or possibly the less oxidized CblC·cob(II)alamin, partitions the cofactor between AdoCbl and MeCbl assimilation pathways.
Keywords	fibroblasts ; genes ; loci ; metabolism ; mutation ; patients ; proteolysis ; vitamin B12
Language	English
Dates of publication	2013-05
Size	p. 1023-1032.
Publishing place	Elsevier Masson SAS
Document type	Article
ZDB-ID	120345-9
ISSN	0300-9084
ISSN	0300-9084
DOI	10.1016/j.biochi.2013.02.003
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Article: Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma.

Zhang, Xi Yun / Rajagopalan, Deepa / Chung, Tae-Hoon / Hooi, Lissa / Toh, Tan Boon / Tian, Johann Shane / Rashid, Masturah Bte Mohd Abdul / Sahib, Noor Rashidha Bte Meera / Gu, Mengjie / Lim, Jhin Jieh / Wang, Wilson / Chng, Wee Joo / Jha, Sudhakar / Chow, Edward Kai-Hua

Experimental hematology & oncology

2020 Volume 9, Page(s) 8

Abstract: Background: Multiple myeloma is an incurable hematological malignancy characterized by a heterogeneous genetic and epigenetic landscape. Although a number of genetic aberrations associated with myeloma pathogenesis, progression and prognosis have been ... ...

Abstract	Background: Multiple myeloma is an incurable hematological malignancy characterized by a heterogeneous genetic and epigenetic landscape. Although a number of genetic aberrations associated with myeloma pathogenesis, progression and prognosis have been well characterized, the role of many epigenetic aberrations in multiple myeloma remain elusive. G9a, a histone methyltransferase, has been found to promote disease progression, proliferation and metastasis via diverse mechanisms in several cancers. A role for G9a in multiple myeloma, however, has not been previously explored. Methods: Expression levels of G9a/EHMT2 of multiple myeloma cell lines and control cells Peripheral Blood Mononuclear Cells (PBMCs) were analyzed. Correlation of G9a expression and overall survival of multiple myeloma patients were analyzed using patient sample database. To further study the function of G9a in multiple myeloma, G9a depleted multiple myeloma cells were built by lentiviral transduction, of which proliferation, colony formation assays as well as tumorigenesis were measured. RNA-seq of G9a depleted multiple myeloma with controls were performed to explore the downstream mechanism of G9a regulation in multiple myeloma. Results: G9a is upregulated in a range of multiple myeloma cell lines. G9a expression portends poorer survival outcomes in a cohort of multiple myeloma patients. Depletion of G9a inhibited proliferation and tumorigenesis in multiple myeloma. RelB was significantly downregulated by G9a depletion or small molecule inhibition of G9a/GLP inhibitor UNC0642, inducing transcription of proapoptotic genes Conclusions: In this study, we demonstrated that G9a is upregulated in most multiple myeloma cell lines. Furthermore, G9a loss-of-function analysis provided evidence that G9a contributes to multiple myeloma cell survival and proliferation. This study found that G9a interacts with NF-κB pathway as a key regulator of RelB in multiple myeloma and regulates RelB-dependent multiple myeloma survival. G9a therefore is a promising therapeutic target for multiple myeloma.
Language	English
Publishing date	2020-05-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2669066-4
ISSN	2162-3619
ISSN	2162-3619
DOI	10.1186/s40164-020-00164-4
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