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Over the past few decades, epigenetic regulators have emerged as major players in cellular processes that drive cancer initiation and progression, and subsequently modulate the responsiveness of cancers to therapeutic agents. This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer. The diverse topics explored herein range from the roles of transposable elements and chromatin architecture in cancer and the most recent research advances on cancer-associated histone variants (oncohistones), to the effects of altered epigenetics on transcription and advanced cancer cell phenotypes. Moreover, the prospective key function of cancer metabolism in linking epigenetics and transcriptional regulation, and the potential of epigenetics for targeted cancer therapeutics is discussed. We hope that this collection of articles will give readers an enlightening overview of the most recent advances in the fast-moving field of cancer epigenetics.

Introduction We have previously shown that although sleep duration is similar between cognitively non-impaired (CNI) elders and patients with Mild Cognitive Impairment (MCI), long sleep duration is associated with disease severity in patients with multi-domain MCI and Dementia. Our aim was to examine the associations between sleep duration and cognitive status in subjects with CNI and MCI followed 8 years later. Methods A sub-sample of 110 participants (77.3% females) were recruited from a large population-based cohort in Crete, Greece of 3,140 older adults (>60 years). Participants with an initial diagnosis of CNI (n=57) and MCI (n=53) (mean age at baseline=72.7 years [SD=6.8]) were followed-up 8 years later (mean age at follow up=80.5 years [SD=6.7]). All participants underwent neuropsychiatric/neuropsychological evaluation (baseline & follow-up) and a 7-day 24h actigraphy (follow-up). Sleep duration measured as night Total Sleep Time (TST) at follow-up was compared between the diagnostic groups using ANCOVA controlling for age, gender, depression symptom severity, psychotropic medication. Long sleep duration was defined by values >75% percentile of the total sample distribution on each sleep index. Results At follow up 62.7% of participants have deteriorated cognitively with 29 being diagnosed with CNI, 49 with MCI and 32 with dementia. Patients with dementia had significantly longer night TST (mean=493, SD=106 min) than persons with MCI (mean=453, SD=68 min, p=0.05) who in turn had longer night TST than CNI participants (mean=409, SD=58 min, p=0.02). Also, long night sleep duration was significantly more prevalent among dementia patients and MCI compared to CNI individuals [67.7% vs. 36.7% vs. 10.3%, respectively; all p< 0.02)]. Conclusion Our study confirms and expands previous findings that objective long sleep duration is a marker of worse cognitive status in elderly with MCI or Dementia and that this association is even stronger in old-old individuals. Support (if any) National Strategic Reference Framework (NSRF)-Research Funding Program: THALES entitled “UOC-Multidisciplinary network for the study of Alzheimer’s Disease” Grant Cod: MIS 377299 HELLENIC FOUNDATION FOR REASEARCH AND INNOVATION (HFRI)- Research Funding Program: ELIDEK entitled “Sleep Apnea (OSA) and poor sleep as Risk Factors for decreased cognitive performance in patients with Mild Cognitive Impairment: the Cretan Aging Cohort (CAC)”, Grant Cod: HFR1-FM17-4397

Anthony Letai is Professor in Medicine at Harvard Medical School and Dana Farber Cancer Institute, and President of The Society for Functional Precision Medicine. Among Tony's scientific achievements, work from his lab contributed toward the FDA approval of Venetoclax combination treatment for adult acute myeloid leukemia (AML) patients. Moreover, his studies on cancer cell death have led to the development of BH3 profiling, an assay that allows for the definition of how close a cell is to the threshold required to commit to apoptosis, which can be used to improve clinical outcomes for cancer patients. In this interview, Tony relays the story behind some of his scientific breakthroughs, discusses the importance of function when designing targeted cancer therapies, gives an overview of BH3 profiling and its application to cancer therapy, and recalls the key events and collaborations that drove his successful research career.

Peter Macheroux is Professor of Biochemistry and Head of the Institute of Biochemistry at Graz University of Technology in Austria. Peter's research spans a diverse selection of topics, and his work has contributed significantly towards advancing our understanding of bacterial enzymology, plant physiology and the molecular pathways that underlie human pathophysiology. Among Peter's many scientific achievements, he has led the team that recognised DPP3 as a biomarker for cardiovascular diseases, with the subsequent therapeutic implications of the development of DPP3 inhibitors. In this interview-based article, Peter provides an overview of his research focus and goals, recalls some of his great scientific breakthroughs and describes what the key current challenges in his research field are.

Introduction Previous cross-sectional studies have shown that insomnia symptoms and objective short sleep are associated with disease severity in patients with Mild Cognitive Impairment (MCI) and Dementia. Our aim was to examine the longitudinal associations between sleep quality/quantity with cognitive progression in non-demented community-dwelling elderly. Methods A sub-sample of 105 participants (77.5% females) from a large population-based cohort in Crete, Greece of 3,140 older adults (>60 years; baseline) were followed up 8 years later (follow-up). All participants underwent neuropsychiatric/neuropsychological evaluation on both phases. At baseline, subjective sleep complaints and objective sleep variables based on 3-day 24 hour actigraphy were assessed. The impact of baseline objective sleep characteristics and/or insomnia (as defined by at least two subjective sleep complaints) on cognitive progression was assessed with univariate and multivariate models controlling for confounders. Results At baseline 50 participants were diagnosed as CNI and 55 as MCI; at follow-up 60 participants (57.1%) displayed clinically significant cognitive deterioration while the remaining showed relatively stable cognitive status. The frequency of persons reporting insomnia symptoms at baseline was higher among those who displayed cognitive deterioration (31.7%) than those in the cognitively stable group (13.3%, p=0.037). Logistic regression analysis showed that participants with insomnia symptoms at baseline, were significantly more likely to deteriorate cognitively at follow-up (p=0.05, OR=2.90). Also, among objective sleep variables added to the model, it was poor sleep efficiency that was associated with cognitive deterioration (p=0.035, OR=3.48). Conclusion More than half of the participants displayed significant cognitive deterioration over 8 years and this decline was predicted by insomnia symptoms and objective poor sleep efficiency at baseline. Improving both quality and quantity of sleep may significantly delay the deterioration of cognitive function in non-demented community-dwelling elderly. Support (if any) National Strategic Reference Framework (NSRF) - Research Funding Program: THALES entitled “UOC-Multidisciplinary network for the study of Alzheimer’s Disease” Grant Cod: MIS 377299 HELLENIC FOUNDATION FOR REASEARCH AND INNOVATION (HFRI)- Research Funding Program: ELIDEK entitled “Sleep Apnea (OSA) and poor sleep as Risk Factors for decreased cognitive performance in patients with Mild Cognitive Impairment: the Cretan Aging Cohort (CAC)”, Grant Cod: HFR1-FM17-4397

Resistance to chemotherapy is a major clinical challenge in breast cancer (BC), and patients developing resistance need treatment alternatives. In this project we utilize patient-derived xenografts (PDXs) from triple negative BC (TNBC), as these models better reflect the human tumor complexity and heterogeneity, compared to cell line-based- and transgene animal models. An in-house established orthotopically growing PDX, MAS98.12, has gained resistance to chemotherapy due to prolonged exposure to paclitaxel (MAS98.12-PR), a microtubule-targeting chemotherapeutic agent. As the resistance was obtained in animals, we also have the paclitaxel sensitive equivalent (MAS98.12-PS). By utilizing the pair of sensitive and resistant tumors we can study the corresponding mechanism evolving in patients who initially respond to chemotherapy before resistance and disease progression. This model will aid in identifying key mechanisms of survival in the resistant tumors, and eventually in identifying targets for use as novel therapeutic opportunities in TNBC patients resistant to standard therapy. Finally, we have samples collected early and late after resistance development, allowing us to characterize mechanisms involved in stepwise progression of paclitaxel resistance. We are currently performing molecular profiling to reveal the mechanisms involved in development of resistance. Data from bulk RNAseq, immune profiling of myeloid cells, exome sequencing, secretome profiling and reverse-phase protein array (RPPA) allow for characterizing the isogenic pair of tumors on multiple levels. Preliminary observations include aberrant expression of ABCB1/MDR1, normally involved in translocating drugs across membranes, and previously described as a mechanism involved in pertaining resistance in tumor cells. As multiple attempts to target MDR1 itself has failed, we hypothesize that our PS and PR pair will identify vulnerable/targetable signaling axis in the resistant tumors. Additionally, both PDX models have been assessed for their sensitivity to various chemo-/targeted-drugs and their combinations, revealing alternative means of treating the resistant tumors. Altogether, the molecular profiles and the sensitivity data will give novel knowledge and treatment options for patients failing to respond to standard chemotherapy. Citation Format: Eivind Valen Egeland, Kotryna Seip, Geir Frode Øy, Eleni Skourti, Solveig J Pettersen, Siri Juell, Mads Haugland Haugen, Olav Engebraaten, Lina Prasmickaite, Gunhild M Maelandsmo. Chemoresistant patient-derived xenografts to identify treatment options in breast cancer patients not responding to standard chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4675.

Identifying modifiable factors that may predict long-term cognitive decline in the elderly with adequate daily functionality is critical. Such factors may include poor sleep quality and quantity, sleep-related breathing disorders, inflammatory cytokines and stress hormones, as well as mental health problems. This work reports the methodology and descriptive characteristics of a long-term, multidisciplinary study on modifiable risk factors for cognitive status progression, focusing on the 7-year follow-up. Participants were recruited from a large community-dwelling cohort residing in Crete, Greece (CAC; Cretan Aging Cohort). Baseline assessments were conducted in 2013–2014 (Phase I and II, circa 6-month time interval) and follow-up in 2020–2022 (Phase III). In total, 151 individuals completed the Phase III evaluation. Of those, 71 were cognitively non-impaired (CNI group) in Phase II and 80 had been diagnosed with mild cognitive impairment (MCI). In addition to sociodemographic, lifestyle, medical, neuropsychological, and neuropsychiatric data, objective sleep was assessed based on actigraphy (Phase II and III) and home polysomnography (Phase III), while inflammation markers and stress hormones were measured in both phases. Despite the homogeneity of the sample in most sociodemographic indices, MCI persons were significantly older (mean age = 75.03 years, SD = 6.34) and genetically predisposed for cognitive deterioration (APOE ε4 allele carriership). Also, at follow-up, we detected a significant increase in self-reported anxiety symptoms along with a substantial rise in psychotropic medication use and incidence of major medical morbidities. The longitudinal design of the CAC study may provide significant data on possible modifiable factors in the course of cognitive progression in the community-dwelling elderly.

Introduction Sleep disturbances have been linked with cognitive decline and previous cross-sectional have shown that long sleep duration is a marker of disease severity in patients Mild Cognitive Impairment (MCI) and Dementia.Our aim was to examine the longitudinal associations between sleep quantity and quality indices and cognitive progression in non-demented community-dwelling elderly. Methods A sub-sample of 62 participants (72.6% females) were recruited from a large population-based cohort in the island of Crete, Greece of 3,140 older adults (>60yrs). Participants were followed-up 8 years later (phase III). All participants underwent neuropsychiatric/neuropsychological evaluation (phases II & III) and a 3-day 24h actigraphy (phase II).Participants were diagnosed as CNI(N=38) and MCI(N=24) during phase II, and CNI (N=22), MCI (N=27) and Dementia (N=13) during phase III. On follow-up, 28 participants progressed to a cognitively declined diagnosis compared to phase II (deteriorated group), while 34 did not (non-deteriorated group). Objective sleep variables at phase II were compared between the deteriotated/non-deteriorated groups using ANCOVA controlling for confounders. Also, differences in neuropsychological testing scores (phase II- phase III) were calculated and associations of differences with sleep variables were examined using partial correlation models controlling for confounders. Results The deteriorated group compared to non-deteriorated had significantly longer night total sleep time (TST) (442±72.6min vs. 407±53.6min, p=0.033), 24h-TST (484±8.9min vs. 434±66.4min, p=0.008), night time in bed (TMB) (537±78.7min vs. 497±62.7min, p=0.03), and 24h-TMB (603±85min vs. 539±85min, p=0.005). Episodic memory worsening was moderately correlated with night TST (r=.316), night and 24h-TMB (r=.526, and r= .442 respectively), wake time after sleep onset (r=.351), and average duration of night awakenings (r=.405). Immediate episodic memory recall decline was positively correlated with night TMB (r=.338). Conclusion Preliminary results from the Cretan aging cohort indicate that almost half of the participants deteriorated cognitively in 8 years and this decline was predicted by objective sleep duration at baseline. Long sleep at baseline may predict deterioration of clinical cognitive status in non-demented elderly at follow-up. It appears that prolonged objective sleep duration and time in bed are novel and clinically useful prognostic factors of cognitive deterioration in elderly with or without cognitive deficits. Support (If Any) National Strategic Reference Framework (NSRF) - Research Funding Program: THALES entitled “UOC-Multidisciplinary network for the study of Alzheimer’s Disease” Grant Cod: MIS 377299HELLENIC FOUNDATION FOR REASEARCH AND INNOVATION (HFRI)- Research Funding Program: ELIDEK entitled “Sleep Apnea (OSA) and poor sleep as Risk Factors for decreased cognitive performance in patients with Mild Cognitive Impairment: the Cretan Aging Cohort (CAC)”, Grant Cod: HFR1-FM17-4397

Professor Dame Janet Thornton has been named as the inaugural recipient of 'The FEBS Journal Open Science Award' for her major role in the development of ELIXIR, the pan-European infrastructure for biological data, as well as the creation of freely available computational tools and knowledge resources.

Super killer (SKI) complex is a well-known cytoplasmic 3′ to 5′ mRNA decay complex that functions with the exosome to degrade excessive and aberrant mRNAs. Recently, SKIV2L, the 3′ to 5′ RNA helicase of the human SKI (hSKI) complex has been implicated in the degradation of nuclear non-coding RNAs escaping to the cytoplasm. Here, we show that hSKI is present in the nucleus, on chromatin and in particular at telomeres during the G2 cell cycle phase. In cells, SKIV2L prevents telomeric loss, and DNA damage response activation, and its absence leads to DNA-RNA hybrid-mediated telomere fragility. Moreover, we demonstrate that purified hSKI complex preferentially unwinds telomeric DNA-RNA hybrids in vitro. Taken together, our results provide a nuclear function of the hSKI complex in overcoming replication stress caused by aberrant processing of telomeric DNA-RNA hybrids and thus maintaining telomere stability.

Telomeres are a significant challenge to DNA replication and are prone to replication stress and telomere fragility. The shelterin component TRF1 facilitates telomere replication but the molecular mechanism remains uncertain. By interrogating the proteomic composition of telomeres, we show that mouse telomeres lacking TRF1 undergo protein composition reorganisation associated with the recruitment of DNA damage response and chromatin remodellers. Surprisingly, mTRF1 suppresses the accumulation of promyelocytic leukemia (PML) protein, BRCA1 and the SMC5/6 complex at telomeres, which is associated with increased Homologous Recombination (HR) and TERRA transcription. We uncovered a previously unappreciated role for mTRF1 in the suppression of telomere recombination, dependent on SMC5 and also POLD3 dependent Break Induced Replication at telomeres. We propose that TRF1 facilitates S-phase telomeric DNA synthesis to prevent illegitimate mitotic DNA recombination and chromatin rearrangement.

The elucidation of the genetic basis of cancer is the result of the research conducted since the beginning of the previous century, which peaked during the decades of 1960s and 1970s. It has been achieved through two different but convergent routes: the first includes the study of oncogenic viruses in rodents and birds and the second includes the use of chemical carcinogens in cells or in animal model systems (mice). Within this framework, the identification of genes that present mutations, alterations in expression levels, and epigenetic modifications has been facilitated through the development of animal carcinogenesis models. One of these models is the well-characterized mouse multistage skin cancer system discussed in this review. In addition, recent evidence shows the great significance that cancer stem cells seem to have in the emergence and progression of carcinogenesis. Finally, herein we discuss the critical role that miRNAs have emerged to play in cancer progression. miRNAs emerged as molecules with an impact on most cancer-related cellular processes, involving cell proliferation, cell death (apoptosis), angiogenesis, migration/motility, and rearrangement of the cytoskeleton. Their discovery has given rise to studies with a focus on miRNAs as key players in crucial oncogenesis-related processes and thus as potential targets in cancer therapeutics.

Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders. The expression pattern of a variety of different microRNAs was investigated in patients (N = 6) suffering from schizophrenia termed control, patients with a solid tumor (N = 10) and patients with both schizophrenia and tumor (N = 8). miRNA profiling was performed on whole blood samples using the miRCURY LNA microRNA Array technology (6th & 7th generation). A subset of 3 microRNAs showed a statistically significant differential expression between the control and the study groups. Specifically, significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumorand schizophrenia) was observed (p