“Escape” from oncogene induced senescence

Η αναστρεψιμότητα της γήρανσης αποτελούσε ένα φαινόμενο αρκετά αμφισβητίσιμο μέχρι πρόσφατα, γι αυτό και οι παράγοντες που οδηγούν σε αυτό το φαινόμενο παραμένουν ασαφείς. Χρησιμοποιώντας ένα ανθρώπινο επιθηλιακό μοντέλο αναπαραστήσαμε ολόκληρο το φάσμα της καρκινογένεσης στον πνεύμονα, που προωθείται από την υπερέκφραση του παράγοντα αδειοδότησης της αντιγραφής CDC6 και περιλαμβάνει το στάδιο της γήρανσης (προκαρκινικό), καθώς και τη διαφυγή του από αυτό (καρκινικό), παρέχοντας αποδείξεις σχετικά με την αυξημένη πολλαπλασιαστική ικανότητα και την επιθετικότητα των κλώνων που διέφυγαν από τη γήρανση. Αυτή η μελέτη επίσης εστιάζει στους γενετικούς και επιγενετικούς παράγοντες που συνέβαλαν ή/και οδήγησαν στο φαινόμενο της επαγόμενης από ογκογόνο διαφυγής από τη γήρανση. Το BHLHE40 ταυτοποιήθηκε ως ένα κρίσιμο γονίδιο, καθώς μία αντιστροφή στον γενετικό τόπο που το κωδικοποιεί προώθησε την τροποποιημένη έκφραση πολλών γονιδίων, ενώ αποδείχθηκε καθοριστικό για την επιβίωση των κυττάρων που διέφυγαν. Πέρα από τις γενετικές αλλοιώσεις, η μη φυσιολογική έκφραση ορισμένων ιστονικών δεικτών, συμπεριλαμβανομένης της ακετυλιωμένης στη λυσίνη 16 ιστόνης 4 (Η4Κ16ac), θα μπορούσε να διευκολύνει το φαινόμενο επηρεάζοντας την έκφραση γονιδίων που σχετίζονται με τη γήρανση και τη διαφυγή από αυτήν. Περαιτέρω έρευνα απαιτείται για την αποσαφήνιση των γενετικών και επιγενετικών παραγόντων που συνεισφέρουν στη διαφυγή από την επαγόμενη από ογκογονίδια γήρανση.The reversibility of senescence has been an issue highly disputable until recently, thus the factors driving this event remain still elusive. Using a human epithelial model, we recapitulate the whole spectrum of lung carcinogenesis, promoted by CDC6 overexpression, including the precancerous (senescent) state and the escape from senescence providing clear evidence about the increased proliferative capacity and aggressiveness acquired by the escaped clones. We also focus on the genetic and epigenetic determinants driving and/or contributing to the phenomenon of the oncogene induced escape from senescence. BHLHE40 was identified as a crucial gene, since an inversion in the region encoding this locus promoted the altered expression of numerous genes while it was found essential for the survival of the escapees. Apart from the genetic alterations, the aberrant expression of histone marks, such as H4K16ac, may facilitate the phenomenon by affecting the expression of genes related to senescence and the evasion from it. Further research is required to delineate the genetic and epigenetic contribution to the escape from oncogene induced senescence

Non-Canonical Functions of the ARF Tumor Suppressor in Development and Tumorigenesis

P14ARF (ARF; Alternative Reading Frame) is an extensively characterized tumor suppressor which, in response to oncogenic stimuli, mediates cell cycle arrest and apoptosis via p53-dependent and independent routes. ARF has been shown to be frequently lost through CpG island promoter methylation in a wide spectrum of human malignancies, such as colorectal, prostate, breast, and gastric cancers, while point mutations and deletions in the p14ARF locus have been linked with various forms of melanomas and glioblastomas. Although ARF has been mostly studied in the context of tumorigenesis, it has been also implicated in purely developmental processes, such as spermatogenesis, and mammary gland and ocular development, while it has been additionally involved in the regulation of angiogenesis. Moreover, ARF has been found to hold important roles in stem cell self-renewal and differentiation. As is often the case with tumor suppressors, ARF functions as a pleiotropic protein regulating a number of different mechanisms at the crossroad of development and tumorigenesis. Here, we provide an overview of the non-canonical functions of ARF in cancer and developmental biology, by dissecting the crosstalk of ARF signaling with key oncogenic and developmental pathways

Interplay of Developmental Hippo–Notch Signaling Pathways with the DNA Damage Response in Prostate Cancer

Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related ‘hubs’ such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR–Hippo–Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis

Regulatory and Functional Involvement of Long Non-Coding RNAs in DNA Double-Strand Break Repair Mechanisms

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis

RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1

RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of gamma-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors

Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy

Abstract Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers

A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that escape from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying escape from oncogene-induced senescence

A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that “escape” from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying “escape” from oncogene-induced senescence