Malat-1 may interact with several tumor suppressor and DNA repair genes and result in cancer
Divya Khatri, and Kiran Kumar Battula*
Keshav Memorial Institute of Commerce and Sciences, Hyderabad – 500029.
*Corresponding author
ABSTRACT
Malat-1 is a long non-coding RNA (lncRNA) over-expressed in several types of cancers. In a large number of studies, its interaction was shown with several micro-RNAs, the degradation of which results in the de-repression of the genes causing cancers. As lncRNAs are known to regulate gene expression by diverse mechanisms, here in the present study we addressed by insilico methods of whether Malat-1 lncRNA has any interaction to sponge away the mRNA of genes, whose repression may lead to cancers. Through these studies, we predicted that Malat-1 lncRNA could interact with the mRNA of several tumor suppressor genes and genes of DNA repair mechanisms. Further in vitro/in vivo studies can lead to a better understanding of these mechanisms and hence on therapeutic aspects.
Received: Dec 05, 2022 | Accepted: Jan 02, 2023 | Published: Jan 05, 2023
Keywords: Malat-1, lncRNA, cancer, tumor suppressor genes, DNA repair genes
Citation: Divya Khatri, and Kiran Kumar Battula (2023) Malat-1 may interact with several tumor suppressor and DNA repair genes and result in cancer. KMICS Journal of Sciences 1(1). https://doi.org/10.62011/kmicsjs.2023.1.1.2
Competing interests: The authors have declared that no competing interests exist.
Copyright: © 2023 Divya Khatri, and Kiran Kumar Battula. This is an open-access article. The use, distribution, and reproduction of this article in any medium is unrestricted, provided the original author and source are cited.
Correspondence: kbattula2@gmail.com
INTRODUCTION
LncRNA, are long non-coding RNAs, of about 200 nucleotides or more in length and some times they may be as long as 100kb 1,2. Like protein-coding genes, they are transcribed by DNA Polymerase II, and most of them are capped, spliced, and polyadenylated3-7. Though generally they are non-coding RNA, some of them have coding potential and code for small functional peptides8-10 . lncRNAs account for more than 16000 genes in mammalian genome, and their major role has been ascribed to regulate gene expression11-15. They employ diverse methods to regulate gene regulation. They may bind to miRNA, mRNA, and even transcription factors and chromatin remodeling proteins to regulate gene expression16-21.
Metastasis-associated lung adenocarcinoma transcript (MALAT)-1 is one of the first cancer-associated lncRNAs to be identified22. It was found to be overexpressed in various types of cancers like nonsmall cell lung cancer (NSCLC), hepatocellular carcinoma, cervical cancer, osteosarcoma, glioblastoma, colorectal cancer, and other cancers23-29. Malat1 is known to be involved in the modulation of several molecular signaling pathways such as MAPK/ERK, PI3K/AKT, WNT/β-catenin, and NF-kB30-34. Therefore malat-1 may have a wide spectrum of interactions. In fact, several studies have shown that Malat-1 interacts with different miRNA, all of which represses the genes causing cancers35.
While malat-1 and miRNA interactions are well known, the direct interaction of Malat-1 with mRNA in the context of cancers is not adequately addressed. Therefore in the present study, through bioinformatics tools, we assessed whether malat-1 has any direct interaction with the mRNA of any of the ‘tumor suppressor genes’, and further with the mRNA of any of the ‘DNA repair genes’ both the types being known to be reduced in cancers.
MATERIALS AND METHODS
- Data mining:
Step1: Tumor suppressor genes and genes for DNA repair mechanisms were obtained from the ‘Gene’ database of the NCBI website (https://www.ncbi.nlm.nih.gov) by providing the respective search words.
Step2: Ensembl IDs for the above genes were obtained from the ‘Ensembl’ website (https://www.ensembl.org) by providing the gene symbols obtained from NCBI. Ensembl ID for ‘Malat-1’ lncRNA was also obtained in a similar way.
- Assessment of Interaction of lncRNA with mRNA of the target genes
“LncRRIsearch”, available at ‘http://rtools.cbrc.jp/LncRRIsearch’ was used to predict the interaction of lncRNA sequence with the mRNA of a target gene upon provision of their ensembl IDs at respective search bars. The tool also provides the length of interaction between the two.
RESULTS
Identification and Shortlisting of ‘Tumor Suppressor Genes’ and genes responsible for ‘DNA repair mechanisms’.
Through the search results from the ‘Gene’ and ‘Pubmed’ databases of NCBI, we have shortlisted 130 genes for the category of tumor suppressor genes and 411 genes for the category of DNA repair genes.
Assessment of interaction of Malat-1 with the above genes
Fifty-five out of 130 tumor suppressor genes (TSGs), and 194/411 DNA repair genes (DRGs) were predicted to interact with the malat 1 gene. Twenty-eight of the DNA repair genes, which were predicted to interact with malat-1, were also found in the list of tumor suppressor genes. Therefore three groups of genes were made which are (i) unique TSGs, (ii) unique DRGs, and (iii) genes common for TSGs & DRGs. Based on the predictions of length of Interaction, the genes were arbitrarily grouped as high (50 bp and above), moderate (18bp-49bp) and low (<18bp) interacting. Among the unique TSGs, 4 genes were predicted as highly interacting, 22 were predicted as moderately interacting and one gene as low interacting. Among the unique DRGs, 40 were predicted as highly interacting, 121 were predicted as moderately interacting, and 5 as low interacting. Among the common genes for TSG and DRG, 7 were predicted as highly interacting, and 21 were predicted as moderately interacting (Table 1).
Table 1: Interaction of Malat-1 with Tumor suppressor genes and DNA repair genes
Unique Tumor suppressor genes (TSGs) | |
High interaction | ZFHX3, EI24, KMT2D, XIRP1 |
Moderate Interaction | CYLD,ERBB4,TBX3,TIMP3,TRIB2,POU2F3,SORBS3,ZAP70, PTGS2,RPS6KA6,
CHD4,CTNNA3,SMARCB1,DNMT3B,NF1,CDKN1B, CSRNP1,CLDN2,ZFP36, DIDO1,RET,TNFRSF10B |
Low Interaction | ID1 |
Unique DNA repair genes (DRGs) | |
High Interaction | HIC1,NONO,SOX4,DTNA,PRRX1,CDK9,CD4,PIK3R2,POGZ,ATXN3,SMAD2,
HNRNPA1,TRIP12,RFC2,HDAC10,XIST,CDK12,MYB,RUNX1,ARRB1,CUX1, LMNA,NCOR2,ASCC1,HUWE1,IRS1,EWSR1,PHF2,POLR2A,ERG,POLK,RUVBL2, KAT5,RPS6KA3,SETD2,UBR5,SQSTM1,XRCC1,CHD2,MAPK3 |
Moderate Interaction | CEP164,ERCC6,FGF2,KIF16B,BCR,DROSHA,EP300,TRRAP,MAPK8
ATM,FTO,IGF1R,PML,TBX20,TREX1,ARID1B,GEMIN4,KMT2C,VDR,DDR1, DDX3X,E2F1,FUS,NIPBL,WT1,ARID1A,MACROD2,POLE,MTUS1, TDP1,XRCC3,PGK1,SPARC,SPTAN1,TET2,ARID2,RAD50,CDK4,DUOX2, NKX21,RAD51,RAG2,SRSF2,BBC3,CLU,CREBBP,EYA1,MRE11A,POLG, SRC,TK2,AKT3,GSK3B,MACF1,RAD54L,SERPINE1,ARL11,DEK, ERCC1,ESR1,MST1R,NR1H3,RELA,SLX4,SMCHD1,TRAF3,BCL2,CCND1, CREB1,TP63,UBA1,ABL1,ACLY,FOS,KRAS,MCM3AP,NPM1,SREBF1, VAV2,BUB1B,EYA2,FANCD2,REV3L,RORC,SOX2,ATXN7,CLIP1, EIF4G1,SMC1A,TERT,HNRNPC,POLL,ATRX,CDK6,CEBPA,ENG,GAPDH, NCOA3,PAK4,VEGFA,ATF3,ING1,APPL2,KIF1A,MGMT,RAD51C,ATR,PIM1, CDK5RAP2,CHRNA4,MAPK1,MPLKIP,SNCA,DICER1,ROCK1,SUZ12, PDS5B,CSNK2A1,GFI1,FANCA,UBC
|
Low Interaction | POLN,SMO,SYNE2,UBE2B,HTT |
Genes common for TSGs & DRGs group | |
High interaction | DNMT3A,SIRT1,AR,EGR1,DOT1L,SP1,YY1 |
Moderate Interaction | SMAD3,PTCH1,STAT3,CDKN1A,CDKN2A,CHEK2,MBD1,SMAD4,KDM5B,
EYA4,PTEN,BRAF,TGFB1,FBXW7,TP73,MYC,MTHFR,TP53,PBRM1, HNRNPA2B1,DNMT1 |
Low Interaction | – |
DISCUSSION AND CONCLUSION
It has been well established that tumor suppressor genes and several of the DNA repair genes are downregulated in cancer conditions (Tables 2, 3). For several of these genes, the mechanisms causing their downregulation, and further the pathways affected are also known. However, as new markers are discovered, they lead to a better understanding on the previous mechanisms. Malat-1 being a relatively new marker needs an exploration of its interaction with all the known genes, whose repression may lead to cancer. While invivo and invitro studies have led to understanding of its interaction with several genes, they are limited to a specific genome variant and a specific prevailing environment. The present bioinformatic analysis attempts to predict Malat-1 interaction with its target genes without such biases. The present work enlists a large number of genes of TSGs, and DRGs groups, which are likely to interact with Malat-1. Validation of these interactions through invitro studies may lead to discovery of new markers and hence novel therapeutic targets.
Table 2: Tumor Suppressor Genes reported as downregulated in various cancers
Gene | Cancer type | Reference |
ZFHX3 | prostate cancer | PMID: 34953044 |
KMT2D | lung tumorigenesis | PMID: 32243837 |
CLDN2 | cancer, primary tumor cells | PMID: 31726679;PMID: 30349422 |
EI24 | Esophageal squamous cell carcinoma, epithelial tumor cells | PMID: 32974192;PMID: 24280371 |
POU2F3 | Small cell lung cancer | PMID: 35760287 |
RPS6KA6 | endometrial cancer | PMID: 21372219 |
AR | breast cancer | PMID: 29912871 |
CDKN1A | breast cancer | PMID: 31169265 |
CDKN2A | colon cancer | PMID: 25879218 |
CHEK2 | breast and other cancers | PMID: 34903604 |
DNMT1 | esophageal cancer | PMID: 30735457 |
DOT1L | ovarian cancer | PMID: 30899413 |
EGR1 | breast cancer | PMID: 34488929 |
CYLD | melanoma | PMID: 34497368 |
CDKN1B | colorectal cancer | PMID: 26114183 |
HNRNPA2B1 | colorectal cancer | PMID: 32698890 |
ID1 | adenocarcinoma gastric cell line | PMID: 23900621 |
KDM5B | breast cancer, acute myeloid leukemia(AML) | PMID: 32003509;PMID: 35217626 |
PBRM1 | cancers | PMID: 33888468 |
PTEN | head and neck cancers | PMID: 26916897 |
TIMP3 | gastric cancer | PMID: 27314831 |
TP53 | cancers | PMID: 27280975 |
Table 3: DNA Repair Genes reported as downregulated in cancers
Genes | cancer type | Reference |
AKT3 | Ovarian cancer | PMID: 31703725 |
AR | Breast cancer | PMID: 29912871 |
ARID1A | Several cancers | PMID: 26384299 |
ATM | Colon cancer | PMID: 34369561 |
BBC3 | Head and Neck cancer | PMID: 23220852 |
BCL2 | Breast cancer cells | PMID: 8174112 |
CDKN1A | Breast cancer | PMID: 31169265 |
CDKN2A | Colon cancer | PMID: 25879218 |
CHEK2 | Breast and Other cancers | PMID: 34903604 |
DNMT1 | Esophageal cancer | PMID: 30735457 |
DOT1L | Ovarian cancer | PMID: 30899413 |
EGR1 | Breast cancer | PMID: 34488929 |
HNRNPA2B1 | Colorectal cancer | PMID: 32698890 |
KDM5B | Breast cancer, Acute myeloid leukemia(AML) | PMID: 32003509;PMID: 35217626 |
PBRM1 | Cancers | PMID: 33888468 |
PTEN | Head and Neck cancers | PMID: 26916897 |
TP53 | Cancers | PMID: 27280975 |
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