S-adenosylmethionine in treatment of cholestasis after total parenteral nutrition: laboratory investigation and clinical application

Objective: To observe the effects of S-adenosylmethio-nine (SAMe) in the treatment of cholestasis after totalparenteral nutrition (TPN).Methods: Thirty SD rats were randomly divided intocontrol group, hypercalorie group, hypercalorie+SAMegroup, sepsis group and sepsis+SAMe group to com-pare their states of cholestasis. Sixteen patients re-ceived SAMe because of cholestasis after prolongedTPN, and the therapeutic efficacy was observed.Results: Bile flow was obviously decreased and theserum levels of total bile acid and gamma-glutamyltranspeptidase(γ-GT) were markedly increased in thehypercalorie and sepsis groups. Meanwhile, hepatocytefatty degeneration, dilatation of cholangioles, and bilesludge could be seen microscopically. SAMe adminis-tration in the hypercalorie+SAMe and sepsis+SAMegroups could increase the bile flow, decrease theserum levels of total bile acid and γ-GT, reduce thepathological damage to the liver, and clear the bilesludge in the cholangioles. Cholestasis and abnormalliver function were the main manifestations of the 16patients before SAMe administration. After SAMe treat-ment for 3 weeks, serum levels of total bilirubin, al-kaline phosphatase(AKP), γ-GT, alanine aminotrans-ferase(ALT), and aspartate aminotransferase(AST)were obviously decreased, and normalized in the 4thweek.Conclusion: SAMe could prevent and treat cholestasiswithout discontinuation of TPN.

Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.

A Prospective, Open-Label, 12 Week Trial of S-adenosylmethionine in the Symptomatic Treatment of Alzheimer’s Disease

Objective: To determine if treatment with S-adenosylmethionine (SAM-e) might lead to cognitive and behavioral improvement in patients with Alzheimer’s disease (AD). Interventions: We conducted a prospective, open-label study of six subjects who were given oral SAM-e over 12 weeks and measured the effects on cognition and behavior. Outcome measures: Outcome measures of cognition and behavior included the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), Behave-AD, Clinical Global Impression Scale (CGI), Hamilton Rating Scale for Depression (HAM-D), informant version, Blessed Dementia Scale to assess activities of daily living (ADL), the Physical Self-Maintainance Scale (PSMS), and the Lawton-Brody IADL Scale to measure instrumental activities of daily living. Results: At study completion, two subjects were “moderately improved” and 4 were “minimally improved” on the CGI. Five subjects improved on the ADAS-Cog by an average of 20%. No significant side effects were reported. Conclusions: In this small open label study, SAM-e appeared to have a beneficial effect in patients with AD, but the small subject number didn’t provide enough power to show statistical significance. Controlled trials with adequate statistical power to investigate its utility in AD are warranted.

产γ-氨基丁酸乳酸菌的筛选及初步鉴定

γ-氨基丁酸是哺乳动物体内的一种抑制性神经递质,具有许多重要的生理功能。利用MRS培养基从自然生境中分离了1000余株细菌,经纸层析和HPLC检测,发现其中一株能转化谷氨酸钠生成GABA,产量为4.84g/L;转化产物通过HPLC-MS得到了证实。通过形态特征和生化特性鉴定,初步判断该菌为乳酸菌。

刚毛柽柳腺苷甲硫氨酸脱羧酶(ThSAMDC)基因的克隆与胁迫下的表达分析

S-腺苷甲硫氨酸脱羧酶(S-adenosyl-L-methionine decarboxylase,SAMDC)是一种通过参与多胺的代谢途径来调节植物生理生化过程的限速酶。通过分析刚毛柽柳(Tamarix hispida)的转录组数据,获得并克隆了SAMDC基因的c DNA序列,将其命名为ThSAMDC。该cDNA序列全长2 085 bp,包含tiny ORF(tORF)、upstream ORF(uORF)和main ORF(mORF)3个植物SAMDC基因特征ORF。主开放读码框(mORF)长1 107 bp,编码369个氨基酸多肽,相对分子质量为40.34 k D,理论等电点(PI)为4.72。Th SAMDC编码蛋白具有多个较强的亲水性区域,无明显跨膜区。通过与其他多个物种的氨基酸多序列比对结果表明,ThSAMDC具有两个典型的高度保守的结构域:酶原剪切位点(LSESSLF)与蛋白快速降解有关的PEST(TIHVTPEDGFSYAS)结构域。系统发育树结果表明ThSAMDC与菠菜(SoSAMDC)氨基酸序列一致性最高,为77%。实时荧光定量RT-PCR分析显示,ThSAMDC在NaCl、PEG、ABA、CdCl_2诱导表达均上调,预示着ThSAMDC可能在刚毛柽柳非生物胁迫应答过程中发挥重要作用。

2型糖尿病患者GAD抗体和血脂检测及意义

目的探讨谷氨酸脱羧酶(GAD)抗体及血脂检测在2型糖尿病(DM2)患者中的临床意义。方法采用放射免疫分析(RIA)、酶法及免疫透射比浊法分别检测了53例DM2患者和30例正常对照组的GAD抗体、胆固醇(CH)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A1(apoA1)及载脂蛋白B(apoB)。结果DM2组GAD抗体阳性率为9.4%,其CH、TG、LDL-C及apoB水平均显著高于正常对照组(P<0.05),而两组间HDL-C及apoA1水平无明显差异(P>0.05)。结论DM2患者少数存在胰岛β细胞功能损伤且普遍继发血脂代谢紊乱,为临床施以有效治疗以及预防、减少并发症发生提供参考依据。

糖尿病患者谷氨酸脱羧酶抗体测定的价值

目的探讨糖尿病患者谷氨酸脱羧酶抗体（GAD—Ab）的检出率及其对糖尿病分型的诊断价值。方法采用酶联免疫法检测98例糖尿病患者、20例正常对照者血谷氨酸脱羧酶的抗体水平，统计T。DM组、T2DM非肥胖组、％DM肥胖组、正常对照组共4组研究对象的谷氨酸脱羧酶抗体的检出率，比较每种抗体各组间的阳性率，另外比较两种抗体同时阳性的比率。结果①T1DM组、T2DM非肥胖组、T2DM肥胖组GAD—Ab检出率分别为70．0％、6．3％和5．6％；ICA检出率分别为68％、8．8％、7．2％；GAD—Ab和ICA同时阳性的几率为68％。②糖尿病各组的检出率分别与正常组比较，P〈0．01，差异有显著性。③T-DM组的检出率分别与T2DM两组比较．均P〈0．05，差异有统计学意义。④T2DM两组问检出率比较，P〉0．05，差异无统计学意义。结论GAD—Ah是1型糖尿病自然病程中B细胞功能损伤的一个指标，对糖尿病预测、分型、指导治疗、判断预后等具有一定的意义。

rAAV2-hGAD65重组载体的构建和功能检测

目的构建rAAV2-hGAD65重组载体,观察其体内外功能。方法应用RT-PCR的方法克隆hGAD65基因,与AAV载体连接得到重组载体(rAAV2-hGAD65)。包装重组腺相关病毒并检测病毒的滴度。体外感染成纤维细胞后,用免疫组织化学的方法检测GAD65在细胞中的表达水平,用高效液相色谱(HPLC)法检测培养上清中γ-氨基丁酸(GABA)的含量。在体实验中,向丘脑底核(STN)立体定位注射rAAV2-hGAD65后,用HPLC方法检测黑质网状部(SNr)中的GABA含量。结果应用RT-PCR方法成功地从人胚胎端脑组织中克隆出GAD65基因的cDNA,基因测序显示与基因库中人GAD65基因序列一致,亚克隆入AAV载体并包装后所得的病毒颗粒的滴度达到4.5×1011/ml。组织化学检测感染大鼠肺成纤维细胞的效率约为80%,HPLC检测培养上清中GABA的含量为(45.66±6.07)nmol/L。STN立体注射rAAV2-hGAD65后,在STN可以检测到hGAD65的表达,SNr区GABA的含量由原来的(5.66±1.07)nmol/g升高到(12.66±2.59)nmol/g。结论成功地克隆出了人GAD65基因,并构建了AAV重组载体。AAV病毒颗粒在体外能感染成纤维细胞并具有催化谷氨酸合成GABA的功能。在体内实验中,向STN注射rAAV2-hGAD65后,可以增加黑质网状部(SNr)中的GABA含量。

Grave’s病患者血清IAA、ICA、GADA的测定及意义

目的测定Graves病患者血清中IAAI、CA、GADA的水平并进一步探讨其意义。方法2003—2004年在我院新诊断的Graves病患者54例,分别测定患者空腹血糖、OGTT 2h血糖,并以ELISA方法测定其血清IAAI、CA、GADA。结果54例Graves病患者中检出糖耐量减退(IGT)患者8例,糖尿病(DM)患者3例。IAAI、CA、GADA阳性率分别为3.7%、9.26%、11.1%。结论ICA、GADA与Graves病有关,但不是病人出现血糖异常的主要原因。

构建杂化酶体系解析对羟基苯乙酸脱羧酶小亚基的功能

对羟基苯乙酸(HPA)脱羧酶是一类甘氨酸自由基脱羧酶,催化前体对羟基苯乙酸或吲哚乙酸的脱羧反应,形成终产物对羟基甲苯和对甲基吲哚。由于其蛋白质结构中小亚基(HpdC)的存在,使其显示了一些不同于其他已知的几种甘氨酸自由基体系的特性,被认为是一类新型的甘氨基自由基酶体系。前期的研究结果初步显示了HpdC在整个脱羧酶体系中的重要性,但缺乏系统的实验验证。通过构建系列杂化脱羧酶(包括组合杂化酶体系与嵌合杂化酶体系)高表达质粒,对相应的编码蛋白质进行分离纯化以及酶活性检测等,探究了小亚基在整个脱羧酶体系中的功能。研究结果证明,小亚基HpdC的存在,一方面直接影响整个编码蛋白质的溶解性及复合物的稳定性,另一方面则通过介导脱羧酶高级聚合状态的形成,决定着酶的催化活性。

Biomarkers and subtypes of deranged lipid metabolism in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.

Methionine adenosyltransferases in liver cancer

Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.

Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells

Methionine adenosyltransferase Ⅱ（MAT Ⅱ） is a key enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine （SAMe） from L-methionine and ATE Normal resting T lymphocytes have minimal MAT Ⅱ activity, whereas activated proliferating T lymphocytes and transformed T leukemic cells show significantly enhanced MAT Ⅱ activity. This work was carried out to examine the role of MAT Ⅱ activity and SAMe biosynthesis in the survival of leukemic T cells. Inhibition of MAT Ⅱ and the resultant decrease in SAMe levels enhanced expression of FasL mRNA and protein, and induced DISC （Death Inducing Signaling Complex） formation with FADD （Fasassociated Death Domain） and procaspase-8 recruitment, as well as concomitant increase in caspase-8 activation and decrease in c-FLIPs levels. Fas-initiated signaling induced by MAT Ⅱ inhibition was observed to link to the mitochondrial pathway via Bid cleavage and to ultimately lead to increased caspase-3 activation and DNA fragmentation in these cells. Furthermore, blocking MAT 2A mRNA expression, which encodes the catalytic subunits of MAT Ⅱ, using a small-interfering RNA approach enhanced FasL expression and cell death, validating the essential nature of MAT Ⅱ activity in the survival of T leukemic cells.

Histone modifications and alcohol-induced liver disease:Are altered nutrients the missing link?

Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.

Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically

AIM： TO examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.METHODS： Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 （Bortezomib, Velcade^TM） by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei.RESULTS： Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation.CONCLUSION： The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption.

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

AIM To investigate the hypothesis that exposure to guanidinoacetate(GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.METHODS Adult male Wistar rats were fed the control or ethanolLieber De Carli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macroand micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

Oxidative stress modulation in hepatitis C virus infected cells

Hepatitis C virus(HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is triggered when the concentration of oxygen species in the extracellular or intracellular environment exceeds antioxidant defenses. Cells are protected and modulate oxidative stress through the interplay of intracellular antioxidant agents, mainly glutathione system(GSH) and thioredoxin; and antioxidant enzyme systems such as superoxide dismutase, catalase, GSH peroxidase, and heme oxygenase-1. Also, the use of natural and synthetic antioxidants(vitamin C and E, N-acetylcysteine, glycyrrhizin, polyenylphosphatidyl choline, mitoquinone, quercetin, S-adenosylmethionine and silymarin) has already shown promising results as co-adjuvants in HCV therapy. Despite all the available information, it is not known how different agents with antiviral activity can interfere with the modulation of the cell redox state induced by HCV and decrease viral replication. This review describes an evidence-based consensus on molecular mechanisms involved in HCV replication and their relationship with cell damage induced by oxidative stress generated by the virus itself and cell antiviral machinery. It also describes some molecules that modify the levels of oxidative stress in HCV-infected cells.

Prostate Specific Antigen Promoter-Driven Adenovirus-Mediated Expression of Both ODC and AdoMetDC Antisenses Inhibit Prostate Cancer Growth

Objective：To generate recombinant adenovirus that could simultaneously express ornithine decarboxylase（ODC） and S-adenosylmethionine decarboxylase（AdoMetDC） antisenses specifically in prostate cancer cells,and evaluate its inhibitory effect on prostate cancer in vivo.Methods：Fragments of ODC and AdoMetDC genes were generated by PCR,cloned into the pPGL-PSES,and then recombined with pAdEasy-1 vectors in AdEasy-1 cells.Ad-PSES-ODC-AdoMetDCas virus was produced in HEK293 cells.Following transfection with Ad-PSES-ODC-AdoMetDCas,the levels of ODC or AdoMetDC were determined by RT-PCR and western blot assays.The effect of Ad-PSES-ODC-AdoMetDCas treatment on tumor formation and growth was evaluated in xenograft models of prostate cancers in vivo.Results：The plasmid pAdEasy-PSES-ODC-AdoMetDCas was successfully constructed and the recombinant Ad-PSES-ODC-AdoMetDCas adenovirus was produced.Transfection with Ad-PSES-ODC-AdoMetDCas adenovirus significantly inhibited the expression of ODC and AdoMetDC genes specifically in prostate DU145 cells,but not H1299,HT29 and HepG2 cancer cells,and disrupted the ability of DU145 cells to form solid prostate cancer in vivo.Intratumoral treatment with Ad-PSES-ODC-AdoMetDCas adenovirus significantly inhibited the growth of engrafted prostate tumors in vivo.Conclusion：The recombinant Ad-PSES-ODC-AdoMetDCas adenovirus specifically reduces the expression of both ODC and AdoMetDC genes in prostate cells and may be used for treatment of prostate cancers at the clinic.

PDRG1 at the interface between intermediary metabolism and oncogenesis

PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.