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The Influence of Epigenetic Modifications on the Expression of SPINT1 and SPINT2 in Colorectal Cancer Cell Lines

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The Influence of Epigenetic Modifications on the Expression of SPINT1 and SPINT2 in Colorectal Cancer Cell Lines The influence of epigenetic modifications on the expression of SPINT1 and SPINT2 in colorectal cancer cell lines Master thesis 2017 Molecular and medicinal biology Mathilde Charlotte Schmidt 50324 Roskilde University, INM Supervisor: Cathy Mitchelmore (Promega Biotech AB 2017) ABSTRACT Hepatocyte growth factor (HGF) has been implicated in carcinogenesis due to its mitogenic, motogenic, and morphogenic activities. Its activator, hepatocyte growth factor activator (HGFA), is inhibited by HGF activator inhibitor-1 (HAI-1) and -2, which are encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) and -2 genes, respectively. Due to their ability to indirectly regulate HGF activity, SPINT1 and -2 are presumed tu- mour suppressor genes (TSGs). In healthy cells, TSGs are involved in regulating cellular processes such as cell division and apoptosis, but in cancerous cells their activity is altered, enabling the cell to avoid the checkpoints involved in those processes. Such alterations can be caused by epigenetic changes, such as DNA methylation and/or histone modifications, which affect the gene expression, but not the gene sequence. The SPINT genes have previously been shown to be downregulated in several cancers due to epigenetic changes. In this study, the aim was to examine the genes for epigenetic changes in colorectal cancer (CRC), which is one of the leading causes of cancer-related death. A methyl specific PCR (MSP) was performed to examine the promoter regions for DNA methylation while a chromatin immunoprecipitation (ChIP) was per- formed to examine for the presence of acetylated histone H3. DLD-1, HCT116, LoVo, and SW480 cells were all used in the MSP, while ChIP was only performed on LoVo cells. The LoVo cells were additionally treated with 5µM 5-aza-2′-deoxycytidine (5-aza), an inhibitor of DNA methyltransferases (DNMT), and 0.1 or 0.3µM tri- chostatin A (TSA), a histone deacetylase inhibitor, to examine if the potential epigenetic changes were reversi- ble. The gene expression was examined in all cell lines as well as the treated LoVo cells through a reverse transcription quantitative PCR (RT-qPCR) and the HAI-2 protein content was examined through a western blot. The expression of SPINT1 and -2 was upregulated in DLD-1 and SW480, downregulated in LoVo, and un- changed in HCT116, compared to a healthy colon sample. The promoter regions did not appear to be methyl- ated in any of the cell lines, but in LoVo cells the promoter regions appear to be partly deacetylated. Treatment with 5-aza generated varying results for expression of both genes, making it difficult to determine the effect. The TSA treatment on the other hand might be useful in restoring SPINT2 expression in LoVo cells, but for SPINT1, the effect was more uncertain. It was not possible to distinguish between the HAI-2 content in the different TSA samples on the western blot, but for the 5-aza samples, only the untreated control generated a band. The protein concentration used for DLD-1, HCT116, and SW480 was too low for the HAI-2 antibody to bind, and it is consequently not possible to comment on their HAI-2 content. Collectively this suggests SPINT1 and -2 are epigenetically changed in LoVo cells, in a manner that might be reversible. Further studies are however needed to verify these observations. Page 1 of 76 RESUME Hepatocyte growth factor (HGF) er grundet dens evne til at inducer blandt andet celledeling og cellebevægelse associeret med cancer. Den aktivers af heptocyte growth factor activator (HGFA), som inhiberes af HGF acti- vator inhibitor-1 (HAI-1) and -2, der er kodet i genomet af serine protease inhibitor Kunitz type 1 (SPINT1) and -2, respektivt. Grundet deres evne til indirekte at regulerer HGF aktiviteten, er de formodet tumor hæm- mende gener (TSGs). TSGs er i raske celler involveret i reguleringen af processer som celledeling og apoptose, men i cancerramte celler er deres aktivitet ændret så de kan undgå reguleringen. Sådanne ændringer kan skyldes epigenetiske forandringer, såsom DNA methylering og/eller histon modifikationer, som påvirker gen- udtrykket, men ikke genomet. SPINT generne er tidligere vist til at være nedreguleret i forskellige cancerformer grundet epigenetiske foran- dringer. Formålet med dette studie var at undersøge generne for epigenetiske forandringer i tyktarmscancer (CRC), som er en af de ledende årsager til cancer relateret død. Methyl specifik PCR (MSP) blev udført for at undersøge promoter regionerne for DNA methylering og kromatin immunoprecipitation (ChIP) blev udført for at undersøge for acetylerede histon H3 i promoter regionerne. DLD-1, HCT116, SW480, og LoVo celler blev alle brugt i MSP, mens kun LoVo cellerne blev brugt til ChIP. Ydermere blev LoVo cellerne behandlet med 5µM 5-aza-2′-deoxycytidine (5-aza), en hæmmer af DNA methyltransferaser (DNMT), og 0,1 eller 0,3µM trichostatin A (TSA), som hæmmer histon deacetylaser, for at undersøge om de epigenetiske forandringer var reversible. Genudtrykket i cellelinjer blev undersøgt via revers transskription kvantitativ PCR (RT-qPCR) og HAI-2 protein mængden undersøgt via western blot. Genudtrykket af SPINT1 og -2 var opreguleret i DLD-1 og SW480, nedreguleret i LoVo, og uændret i HCT116, sammenlignet med en sund kolon kontrol. Promoter regionerne fremgår ikke til at være methyleret i nogle af cellelinjerne, men er muligvis delvist deacetylerede i LoVo celler Behandling med 5-aza genererede forskellige resultere for udtrykket af begge gener, så det er svært at konkluderer på effekten. TSA behandlingen derimod virker til at være brugbar til at gendanne genudtrykket af SPINT2, hvorimod effekten på SPINT1 udtrykket er mere usikker. Det var ikke muligt at skelne i mellem HAI-2 indholdet i de forskellige TSA prøver på western blottet, men for de 5-aza behandlede celler var det kun den ubehandlede prøver der gav et bånd. For DLD-1, HCT116, and SW480 var protein koncentrationen for lav til HAI-2 antistoffer kunne bind, og der er som følge ikke muligt at sige noget om HAI-2 indholdet i de celler. Resultaterne af dette stude indikerer SPINT1 og -2 er epigenetisk forandret i LoVo celler, på en måde der muligvis er reversible. Yderligere studier er dog nødvendige for at bekræfte disse observationer. Page 2 of 76 CONTENT ABSTRACT ....................................................................................................................................................................... 1 RESUME ............................................................................................................................................................................ 2 1. INTRODUCTION ........................................................................................................................................................ 5 1.1 Epigenetics .............................................................................................................................................................. 6 1.1.1 DNA methylation ............................................................................................................................................ 6 1.1.2 Histone modifications ..................................................................................................................................... 9 1.2 Epigenetics and cancer ........................................................................................................................................ 10 1.2.1 Colorectal cancer ............................................................................................................................................ 11 1.3 HAIs, HGFA, and HGF ....................................................................................................................................... 12 1.3.1 Hepatocyte growth factor activator inhibitors .......................................................................................... 13 1.3.2 Hepatocyte growth factor activator ............................................................................................................ 15 1.3.3 Hepatocyte growth factor ............................................................................................................................. 16 1.4 Aims and objective ............................................................................................................................................... 21 2. METHODS AND MATERIALS ............................................................................................................................... 22 2.1 Cell culture ............................................................................................................................................................ 22 2.1.1 Subculturing ................................................................................................................................................... 22 2.1.2 5-aza-2’-deoxycytidine treatment ................................................................................................................ 22 2.1.3 Cross-linking .................................................................................................................................................. 23 2.1.4 Trichostatin A treatment ............................................................................................................................... 23 2.2 Reverse Transcription quantitative PCR ..........................................................................................................
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