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  • br Acknowledgements This research was supported by the Natur

    2021-09-09


    Acknowledgements This research was supported by the Natural Sciences and Engineering Council of Canada (NSERC) Discovery Grant awarded to RGM. LMW was supported in part by fellowships from the University of Regina and the Government of Saskatchewan Fish and Wildlife Development Fund (FWDF). We would like to thank Lori Manzon for help with cloning, Andrea Murillo for statistical support and Dr. Rebecca North from the University of Missouri for providing data on oxygen levels in Blackstrap Lake, SK.
    Introduction Glioblastoma Multiforme (GBM), an aggressive tumor of the adult central nervous system, is the most malignant of glial neoplasm representing up to 50% of all primary Fmoc-Thr(tBu)-OH gliomas [1]. GBMs tumors are characterized by intratumoral genetic heterogeneity and remarkable ability to invade surrounding normal brain tissues, thus evading total surgical resection as well as radiation treatments and chemotherapy [1,2]. Despite continuous and significant advances in clinical therapies for the treatment of GBM, the patient prognosis is poor and after initial diagnosis the medial survival duration is about 9–12 months, suggesting urgently the need for the development of novel therapeutic strategies [3]. GBMs have alterations in cell-cycle checkpoints, senescence and apoptosis pathways, giving rise to uncontrolled cell proliferation [2,4]. An important mechanism for preventing proliferation in tumor cells is the stress-responsive senescent cellular program, a state in which the cell is no longer able to proliferate [5]. Senescent cells have irreversibly lost their capacity for cell division, although senescent cells are vital and metabolically active [[5], [6], [7]]. Senescence process is characterized by several non-exclusive markers, such as the absence of proliferative signals, induction of growth arrest markers, β-galactosidase activity associated with senescence (SA-βgal), expression of tumor suppressors and cell cycle inhibitors and often induction of DNA damage markers [[8], [9], [10]]. The causative role of epigenetic enzymes, as histone deacetylases and demethylases, in the senescence process has been recently documented. It has been shown that Sirtuins regulate premature cellular senescent and accelerate aging [11,12]. Sirtuin proteins constitute class III histone deacetylases (HDACs) with important roles in cellular and biological processes, as well as in metabolic homeostasis and genomic integrity [13]. Loss of Lysine-specific demethylase 1 (LSD1) demethylase activity provokes senescence in trophoblast stem cells [14] and prevents age-programmed loss of beige adipocytes [15]. LSD1/KDM1A is an epigenetic eraser that catalyses lysine demethylation in a flavin adenine dinucleotide (FAD)-dependent oxidative reaction. LSD1 demethylates both Lys-4 (H3K4me/me2) and Lys-9 (H3K9me/me2) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context [[16], [17], [18], [19]]. LSD1 is overexpressed in a variety of human cancers and tends to correlate with more aggressive tumors with poor prognosis [20,21]. In addition, LSD1 can also target several non-histone proteins such as p53 [22], E2F [23], DNMT1 [24] and HIF-1α [25]. Hypoxia-inducible factor 1-alpha (HIF-1α), together with the homonym subunit beta, form a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) [26]. HIF-1α is a basic helix-loop-helix PAS domain containing protein and together with subunit beta binds hypoxia-responsive elements (HREs) that contain a conserved RCGTG core sequence. HIF-1α, under normoxic conditions, undergoes negative regulation via ODD domain [27]. This domain contains a number of prolyl residues that are recognized and hydroxylated by specific prolyl hydroxylase domain (PHD) enzymes; this results in the binding of a key negative regulator of HIF-1α, the von Hippel – Lindau protein (VHL) E3 ligase, which targets the HIF-1α protein for rapid degradation via the proteasome pathway [28].