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  • The stability and function of

    2021-09-07

    The stability and function of the HIF-1α protein are affected by many post-translational modifications (PTMs), including hydroxylation, acetylation, ubiquitination and SUMOylation [[29], [30], [31]]. It has been shown that HIF-1α stability is regulated by LSD1 [25]; in particular, the Set9 histone methyltransferase induces HIF-1α methylation promoting HIF-1α protein degradation, while LSD1 reverses this process [32]. Furthermore, LSD1 upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1α [33]. It has been reported that HIF-1α plays a role in cellular senescent state. Welford et al. highlighted a novel role for HIF-1α to delay premature senescence through the activation of macrophage migration inhibitory factor (MIF) [34]. Others studies propose that inhibition of HIF-1α in combination with ATRA treatments enhances senescent sodium butyrate in RA-responsive cells and silencing of HIF-1α suffices to increase the number of senescent cells independently to the ATRA responsiveness [35].
    Materials and methods
    Results
    Discussion LSD1 is involved in several biological processes, such as cell proliferation [47], epithelial-mesenchymal transition [42,48], pluripotency and stem cell differentiation [49]. Here we report that pharmacological or genetic inhibition of LSD1 induces senescence and reduces proliferation and migration through the regulation HIF-1α protein level. HIF-1α regulates genes that play key roles in cancer-related process, such as proliferation, angiogenesis, apoptosis/autophagy, metabolism, cell migration and invasion [[50], [51], [52]]. Several studies reported a significant relationship between poor prognosis and HIF-1α overexpression in glioma patients and HIF-1α is considered an attractive target for GBM therapy [53,54]. Indeed HIF-1α targeting has been proposed in combination with radiation therapy for GBM treatment [55]. GBM is frequently accompanied by the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway, with the majority of tumors displaying over-expression of the EGFRvIII variant and loss of PTEN [56]. Given the key role of mTORC1 in proliferation and metabolism [57], its aberrant activation contributes to tumor growth, angiogenesis and metastasis [57,58]. We found that LSD1 inhibition hampers the mTORC1 activity in GBM cells and such effect is associated with mitochondrial respiration impairment. Although high glycolysis is a hallmark of cancer, glycolytic cells also rely on mitochondrial intermediates to generate molecules required for tumor growth [59]. Moreover, it has been reported that cancer cells can use OXPHOS during tumor progression or under limiting glucose conditions [60,61]; thus, against Warburg's proposal, an active OXPHOS could be more advantageous for tumors than a completely glycolytic type of metabolism, which suggests the possibility of targeting mitochondria to alter tumor metabolic adaptation and progression [62,63]. HIF-1α regulation is not the only mechanism that connects inhibition of LSD1 and senescence. Telomere shortening and DNA damage lead to cellular senescent [10,64,65] and both these processes are regulated by LSD1 [66,67]. Moreover, Yu et al. show that two different types of H3K9 demethylases, LSD1 and JMJD2C, disable oncogenic-induced senescence by enabling the expression of E2F target genes [68]. Finally, inactivation of LSD1 has been shown to boost senescence in trophoblast stem cells by induction of Sirt4 [14]. Thus, LSD1 appears to be a regulatory hub that controls different aspects of cellular senescent, metabolic pathways and cancer. Senescence induction in cancers may function as a powerful weapon for eradicating tumorigenesis [69]. Therapies that enhance senescence not only promote a stable arrest of cell growth, but also act as a strong stimulus for the activation of the antitumor immune response [70].