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Epigenetic Awakening of Viral Mimicry in Cancer

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Epigenetic Awakening of Viral Mimicry in Cancer VIEWS IN THE SPOTLIGHT Epigenetic Awakening of Viral Mimicry in Cancer Maxime Janin 1 and Manel Esteller 1 , 2 , 3 , 4 Summary: In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation. See related article by Deblois et al., p. 1312 (4). Tumor progression by resistance to pharmacologic ther- and the concomitant signifi cant upregulation of EZH2 in apy is a major issue for managing patients with cancer, with TNBC compared with the other breast cancer subtypes ( 3 ) few treatment alternatives, and is associated with poor prog- makes the study by Deblois and colleagues in this issue ( 4 ) nosis. This is particularly the case for triple-negative breast a useful reference for better drug resistance understanding cancer (TNBC), which initially tends to respond to treatment and therapy development. The mechanism of resistance to but often develops resistance, leading to the advancement therapy pinpointed herein ( 4 ) is the escape from viral mim- of the disease. Thus, deciphering by which mechanism the icry response. This response normally occurs through the cancer cells adapt to the cytotoxic pressure of the drugs is activation of human endogenous retroviral elements (HERV) of utmost importance. During the last decades, efforts by that leads to double-stranded RNA (dsRNA) production and the research community have led to the expansion of tumor IFN-mediated T-cell recognition. In resistant cells, the DNA biomarker discovery, allowing clinicians to choose adequate methylation pattern impedes the retroviral element activa- therapeutic strategies for both original tumors and relapses, tion, and so the use of hypomethylating agents has been which has led to increased patient lifespan. These biomark- shown to reactivate HERVs, leading to apoptosis and tumor ers are present at all levels from DNA to proteins. In this fi eld growth inhibition ( 5, 6 ). of opportunities, epigenetics is gaining importance for diag- In breast cancer, patients with BRCA1 and BRCA2 germline nosis and prognosis but also in the prediction of response to mutations are sensitive to PARP inhibitors, but cell lines with treatment. In this last application, both DNA methylation CpG island methylation of BRCA1 have also been shown to be and histone marks can be reversed by specifi c inhibitors ( 1 ) sensitive to these inhibitors ( 7 ). Comparative studies revealed changing chemosensitivity profi les. For example, the use that germline mutations or CpG island methylation had the of the EZH2 inhibitor tazemetostat (Tazverik) has recently same pattern of gene expression and, overall, a similar phe- been approved by the FDA for patients carrying an activating notype. The authors found that close to 37% of the TNBC EZH2 mutation in advanced or metastatic epithelioid sar- tumors exhibited methylation of BRCA1 , offering a potential coma not eligible for complete resection, and adult patients therapeutic solution for these patients ( 7 ). More recently, it with relapsed or refractory (R/R) follicular lymphoma ( 2 ). was shown in TNBC patient-derived xenograft (PDX) models The ongoing study of tazemetostat and similar drugs in that the tumors, initially sensitive to docetaxel, a type of tax- various clinical trials is also encouraging for other neoplasia ane, contained a resistant subpopulation of CD49f-positive types, and it is an illustrative example of how epigenetics cells, also called integrin α 6, a marker of stem cells ( 8 ). This can initially infl uence prognosis and guides therapy develop- subpopulation is enriched during treatment due to apoptosis ment. In this regard, the recent interest in gene expression of the sensitive cells, which can lead to metastasis and fatal regulation by the H3K27me3 repressive mark in TNBC progression. This context underlines the evolving dimension of tumors, the interplay between the different intratumor subpopulations, and the selective character of tumor treat- 1 Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barce- ments. To avoid the emergence of treatment resistance of lona, Catalonia, Spain. 2 Centro de Investigacion Biomedica en Red Cancer nonresponsive tumor cells due to intratumor heterogeneity, (CIBERONC), Madrid, Spain. 3 Physiological Sciences Department, School single-cell DNA methylation and histone modifi cation profi l- of Medicine and Health Sciences, University of Barcelona (UB), Barce- lona, Catalonia, Spain. 4 Institucio Catalana de Recerca i Estudis Avançats ing ( 9 ) has emerged as a promising tool to identify and study (ICREA), Barcelona, Catalonia, Spain. these clones that can provide clues for possible multitherapy Corresponding Author: Manel Esteller, Josep Carreras Leukaemia Research approaches. Clinically, the need for patient stratifi cation with Institute, Carretera de Can Ruti, Camí de les Escoles, s/n, Badalona, Barce- TNBC is important, and gene methylation signatures can lona 08916, Catalonia, Spain. Phone: 349-3557-2837; E-mail: mesteller@ help to predict how the patients will respond to treatment carrerasresearch.org ( 10 ). Cancer Discov 2020;10:1258–60 In this context, Deblois and colleagues ( 4 ) go a step further doi: 10.1158/2159-8290.CD-20-0947 with the fi nding that metabolic reprogramming, DNA meth- © 2020 American Association for Cancer Research. ylation, and chromatin marks are interdependent to escape 1258 | CANCER DISCOVERY SEPTEMBER 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. VIEWS A B Viral mimicry response TE hypomethylation and expression Paclitaxel TE repression by Viral mimicry H3K27me3 reallocation escape Endogenous retroviral dsRNA SAM metabolism alteration IFIH1 TLR3 Intergenic DNA RIG1 hypomethylation Bind to dsRNA-sensing proteins Paclitaxel Transcription of the IFN gene β EZH2i TE expression IFNβ response Viral mimicry dsRNAs response T-cell activation accumulation Figure 1. The role of epigenetic drugs in the awakening of viral mimicry. A, The general model of viral mimicry response starts by the reexpression of transposable elements (TE) in association with DNA hypomethylation. TE expression leads to dsRNA accumulation that is recognized by sensing proteins such as IFIH1, RIG1, and TLR3. These complexes upregulate the expression of the IFNβ gene, leading to T-cell activation. B, In TNBC, pacli- taxel induces a SAM metabolism alteration that leads to DNA hypomethylation. The repression of TEs is driven by H3K27me3 reallocation and leads to viral mimicry escape (top). Treatment with EZH2 inhibitor (EZH2i) leads to histone mark reduction and to the reactivation of the viral mimicry response (bottom). viral mimicry response. Indeed, the decrease of the universal hypomethylation was enriched in intergenic regions in both methyl-donor S-Adenosyl-Methionine (SAM) metabolism in resistant cell lines and resistant PDXs, and hypermethylation taxane-resistant TNBC cells leads to DNA hypomethylation, marks were mostly found at gene promoter regions associ- which could have a pro-response effect, but the H3K27me3 ated with IFNα/β and cytokine signaling gene signature. reallocation at specific chromatin domains prevents the As SAM is also the methyl donor of histone methyltrans- response activation. ferases, the authors examined whether the levels and the dis- Using paclitaxel-resistant cell line models generated from tribution of the histone marks were affected by methionine the TNBC cell lines, the authors observed that methionine metabolism alteration. The global level was not affected, but metabolism was altered in resistant models compared with the distribution was significantly different between resistant parental cells. This alteration leads to exogenous L-methio- and parental cells, meaning a reallocation of these repressive nine dependency of taxane-resistant cells for proliferation marks. This reallocation leads to close cluster formations and an improved antioxidant capacity. As SAM is the methyl grouped in Large Organized Chromatin Lysine (K) domains donor of the DNA methyltransferases (DNMT), the authors (LOCK). To understand the role of the H3K27me3 marks in investigated whether SAM reduction leads to DNA hypo- LOCKs, they classified them as taxane-resistant or parental methylation. They observed a significant decrease of DNA cells. They identified close to 50% more taxane-resistant methylation in the resistant models relative to the paren- LOCKs compared with the parental ones, but importantly, tal cells. Global DNA hypomethylation was also assayed their average size was more than 20 times wider (630 Kb ver- by identification of differentially methylated regions (DMR) sus 29 Kb), meaning a gain of widespread heterochromatin between taxane-resistant and parental cells. These data were domains over gene-poor regions in taxane-resistant TNBC also confirmed in taxane-resistant PDX models. Importantly, cells driven by H3K27me3 reallocation. By comparing DNA September 2020 CANCER DISCOVERY | 1259 Downloaded from cancerdiscovery.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. VIEWS methylation and H3K27me3 location, the authors found and other issues.
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