Lösemi patogenezinde miRNA 15a/16–1 lokus delesyonlarının ve Protein L-isoaspartate O-methyltransferase (PCMT1) enziminin rolü

Year 2019, , 117 - 122, 04.03.2019

Burcu Biterge-süt , Dilara Fatma Balı

https://doi.org/10.17343/sdutfd.442996

Abstract

Kanser, ülkemizde ve dünyada sıklıkla görülen hastalıklardan birisidir. Karsinojenez
sırasında büyük değişimlere uğrayan hücresel gen ifadesi profili DNA dizisi
dışında DNA metilasyonu, kodlanmayan RNA’lar (ncRNA), RNA interferansı (RNAi),
histon varyantları ve post-translasyonel histon modifikasyonları gibi başkaca epigenetik
mekanizmalar tarafından da kontrol edilebilmektedir. Bununla birlikte; mutasyonlar,
delesyonlar ve translokasyonlar gibi çeşitli sebepler sonucu ortaya çıkan
genetik anomaliler kanser oluşumunda ve tedaviye verilen yanıtta önemli rol
oynamakta ve klinikte, kanser alt tiplerinin belirlenmesinde incelenmektedir. 13.
kromozomun q kolunda bulunan miRNA 15a/16-1 lokusu delesyonlarının Mcl1, Bcl2,
Ets1, Jun gibi kanser ile ilişkili birçok geni etkilediği gösterilmiştir.
Ayrıca, bu miRNA’ların regüle ettiği Protein L-isoaspartate O-methyltransferase
(PCMT1) proteinin apoptoz yolağı üzerindeki etkisi dolayısıyla karsinojenez
üzerinde önemli rol oynadığı birçok çalışma ile vurgulanmıştır. Literatürde
miRNA 15a/16-1 lokusu ve p53 arasında hücre proliferasyonu ve büyümesini
sağlayan sinyallerin üretimini düzenleyen bir feedback döngüsünün varlığı
tartışılmaktadır. Yapılan çalışmalar, miRNA 15a/16-1 lokusunu tümör baskılayıcı
gen bölgesi, PCMT1’i ise onkogen olarak tanımlamaktadır. Buna paralel olarak, miRNA
15a/16-1 lokusunu da içeren 13q14.3 bölgesi delesyonu birçok lenfoid ve
miyeloid lösemi alt türlerinde tespit edilmiş olup, klinikte rutin taramalara
dahil edilme potansiyeline sahiptir. Lösemi hastalarında 13q14.3 bölgesi delesyonunun
araştırılması hastalığın alt tiplerinin sınıflandırılmasını ve hatta
uygulanacak tedavi rejimini yönlendirebilecek önemli sonuçlar elde edilmesini
sağlayabilecektir.

Keywords

Epigenetik, lösemi, apoptoz, miRNA 15a/16–1, delesyon, PCMT1

A new perspective on carcinogenesis: miRNA 15a/16–1 cluster deletions promote cell survival via Protein L-isoaspartate O-methyltransferase (PCMT1) activity

Abstract

Cancer is a commonly
encountered disease both in Turkey and worldwide. Cellular gene expression
profiles that drastically change during carcinogenesis can be regulated via
several epigenetic mechanisms such as DNA methylation, non-coding RNAs (ncRNA),
RNA interference (RNAi), histone variants and post-translational modifications
of histones. In addition to these mechanisms, genetic anomalies that arise due
to various reasons including mutations, deletions and translocations have
significant roles both in carcinogenesis and the response to treatment and are
screened routinely in clinic when determining cancer subtypes. miRNA 15a/16-1
cluster which is located on the q arm of chromosome 13 is often deleted
in cancers and regulates the activity of several cancer-associated genes such
as Mcl1, Bcl2, Ets1, Jun. Furthermore, the role of Protein L-isoaspartate O-methyltransferase
(PCMT1) which is regulated by these miRNAs, in carcinogenesis through its
effects in apoptosis pathway is emphasized by various studies. It is suggested
that there is a feedback loop between miRNA 15a/16-1 cluster and p53
which regulates cellular signals for proliferation and cell survival. Studies
describe miRNA 15a/16-1 cluster as a tumor suppressor, while identifying PCMT1
as an oncogene. In line with this, deletions in the 13q14.3 region which also spans the miRNA
15a/16-1 cluster are detected
in multiple lymphoid and myeloid leukemia subtypes and have the potential to be
included in routine clinical genetic screens. Examining 13q14.3 deletions
in leukemia patients has the potential to yield important results that could be
useful both in determining cancer subtypes and deciding which therapeutic
regime to apply on a single-patient basis.

Keywords

Epigenetics, leukemia, apoptosis, miRNA 15a/16–1, deletion, PCMT1

References

• 1. Huisinga KL, Brower-Toland B & Elgin SC. The contradictory definitions of heterochromatin: transcription and silencing. Chromosoma 2006:115, 110–122.
• 2. Cam HP, Sugiyama T, Chen ES, Chen X, FitzGerald PC, Grewal SI. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat Genet. 2005:37(8):809-19
• 3. Murchison EP, Hannon GJ. miRNAs on the move: miRNA biogenesis and the RNAi machinery. Curr Opin Cell Biol. 2004:16(3):223-9
• 4. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6:857–866.
• 5. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;26;99(24):15524-9.
• 6. Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A. 2008; 105(13):5166-71.
• 7. Aqeilan RI, Calin GA, Croce CM. miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ. 2010; 17(2):215-20. doi: 10.1038/cdd.2009.69.
• 8. Chang H, Bouman D, Boerkoel CF, Stewart AK, Squire JA. Frequent monoallelic loss of D13S319 in multiple myeloma patients shown by interphase fluorescence in situ hybridization. Leukemia 1999; 13: 105–109.
• 9. Wada M, Okamura T, Okada M, Teramura M, Masuda M, Motoji T, Mizoguchi H. Frequent chromosome arm 13q deletion in aggressive non-Hodgkin’s lymphoma. Leukemia 1999; 13:792–798.
• 10. Lens D, Matutes E, Catovsky D, Coignet LJ. Frequent deletions at 11q23 and 13q14 in B cell prolymphocytic leukemia (B-PLL). Leukemia 2000; 14: 427–430.
• 11. Königsberg R1, Ackermann J, Kaufmann H, Zojer N, Urbauer E, Krömer E, Jäger U, Gisslinger H, Schreiber S, Heinz R, Ludwig H, Huber H, Drach J. Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia. 2000 Nov;14(11):1975-9.
• 12. Cave H, Avet-Loiseau H, Devaux I, Rondeau G, Boutard P, Lebrun E, Mechinaud F, Vilmer E, Grandchamp B. Deletion of chromosomal region 13q14.3 in childhood acute lymphoblastic leukemia. Leukemia 2001; 15: 371–376.
• 13. Rowntree C, Duke V, Panayiotidis P, Kotsi P, Palmisano GL, Hoffbrand AV, Foroni L. Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia. Leukemia 2002; 16(7):1267-75.
• 14. Mertens D, Wolf S, Schroeter P, Schaffner C, Döhner H, Stilgenbauer S, Lichter P. Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia. Blood. 2002 Jun 1;99(11):4116-21.
• 15. Wolf S, Mertens D, Schaffner C, Korz C, Döhner H, Stilgenbauer S, Lichter P. B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions. Hum Mol Genet. 2001 Jun 1;10(12):1275-85.
• 16. Mabuchi H, Fujii H, Calin G, Alder H, Negrini M, Rassenti L, Kipps TJ, Bullrich F, Croce CM. Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res. 2001 Apr 1;61(7):2870-7.
• 17. Sánchez-Beato M, Sánchez-Aguilera A, Piris MA. Cell cycle deregulation in B-cell lymphomas. Blood. 2003 Feb 15;101(4):1220-35.
• 18. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9.
• 19. Ogawara M, Takahashi M, Shimizu T, Nakajima M, Setoguchi Y, Shirasawa T. Adenoviral Expression of Protein L-isoaspartyl Methyltransferase (PIMT) Partially Attenuates the Biochemical Changes in PIMT-deficient Mice. Journal of Neuroscience Research 2002; 69, 353-361
• 20. Biterge B. Protein L-Isoaspartate O-Methyltransferase (PCMT1): A Key Player of Spontaneously Arisen Protein Damage Repair. Anatomy Physiol Biochem Int J. 2017; 3(1): 555605.
• 21. Lee JC, Kang SU, Jeon Y, Park JW, You JS, Ha SW, Bae N, Lubec G, Kwon SH, Lee JS, Cho EJ, Han JW. Protein L-isoaspartyl Methyltransferase Regulates p53 Activity. Nature Communications, 2011; 3:927
• 22. Cimmino A, Capasso R, Muller F, Sambri I, Masella L, Raimo M, De Bonis ML, D’Angelo S, Zappia V, Galletti P, Ingrosso D. Protein isoaspartate methyltransferase prevents apoptosis induced by oxidative stress in endothelial cells: role of Bcl-Xl deamidation and methylation. PLoS One 2008; 3(9):e3258
• 23. Young AL, Carter WG, Doyle HA, Mamula MJ, Aswad DW. Structural Integrity of Histone H2B in vivo Requires the Activity of Protein L-isoaspartate O methyltransferase, a Putative Protein Repair Enzyme. The Journal of Biological Chemistry 2001; 276, 37161-37165
• 24. Young GW, Hoofring SA, Mamula MJ, Doyle HA, Bunick GJ, Hu Y, Aswad DW. Protein L-isoaspartyl Methyltransferase Catalyzes in vivo Racemization of Aspartate- 25 in Mammalian Histone H2B. The Journal of Biological Chemistry 2005; 280, 26094-26098
• 25. Carter WG, Aswad DW. Formation, Localization and Repair of L-isoaspatyl Sites in Histones H2A and H2B in Nucleosomes from Rat Liver and Chicken Erythrocytes. Biochemistry 2008;47, 10757-10764
• 26. Biterge B, Richter F, Mittler G, Schneider R. Methylation of histone H4 at aspartate 24 by Protein L-isoaspartate O-methyltransferase (PCMT1) links histone modifications with protein homeostasis. Nature Scientific Reports 2014;4:6674
• 27. Sambri I, Capasso R, Pucci P, Perna AF, Ingrosso D. The microRNA 15a/16-1 cluster down-regulates protein repair isoaspartyl methyltransferase in hepatoma cells: implications for apoptosis regulation. J Biol Chem. 2011;286(51):43690-700
• 28. Liu J, Chen G, Feng L, Zhang W, Pelicano H, Wang F, Ogasawara MA, Lu W, Amin HM, Croce CM, Keating MJ, Huang P. Loss of p53 and altered miR15-a/16-1MCL-1 pathway in CLL: insights from TCL1-Tg:p53(-/-) mouse model and primary human leukemia cells. Leukemia. 2014 Jan;28(1):118-28.
• 29. Dong L, Li Y, Xue D, Liu Y. PCMT1 is an unfavorable predictor and functions as an oncogene in bladder cancer. IUBMB Life, 2018; 70(4):291-299.
• 30. Huang E, Liu R, Chu Y. miRNA-15a/16: as tumor suppressors and more. Future Oncol. 2015;11(16):2351-63.
• 31. Fabbri M, Bottoni A, Shimizu M, Spizzo R, Nicoloso MS, Rossi S, Barbarotto E, Cimmino A, Adair B, Wojcik SE, Valeri N, Calore F, Sampath D, Fanini F, Vannini I, Musuraca G, Dell'Aquila M, Alder H, Davuluri RV, Rassenti LZ, Negrini M, Nakamura T, Amadori D, Kay NE, Rai KR, Keating MJ, Kipps TJ, Calin GA, Croce CM. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA. 2011 Jan 5;305(1):59-67.
• 32. Meyer S, Eden T, Kalirai H. Dexamethasone protects against Cisplatin-induced activation of the mitochondrial apoptotic pathway in human osteosarcoma cells. Cancer Biol Ther. 2006;5(8):915-20.
• 33. Lin KT, Wang LH. New dimension of glucocorticoids in cancer treatment. Steroids 2016;111:84-88.
• 34. Fietz ER, Keenan CR, López-Campos G, Tu Y, Johnstone CN, Harris T, Stewart AG. Glucocorticoid resistance of migration and gene expression in a daughter MDA-MB-231 breast tumour cell line selected for high metastatic potential. Sci Rep. 2017:6;7:43774.
• 35. Schlossmacher G, Stevens A, White A. Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol. 2011;211(1):17-25