Conte, Andrea (2016) HMGA1 knock-down induces autophagy through regulation of ULK gene expression in cancer cells. [Tesi di dottorato]

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High Mobility Group A1 (HMGA1) is a chromatinic protein whose overexpression is a feature of malignant neoplasias. Many studies support its causal role in cell transformation and cancer progression. Indeed, HMGA1 is an architectural transcriptional factor that regulates, by binding DNA and interacting with various transcriptional regulators, the expression of several genes involved in critical biological processes, such as cell proliferation, apoptosis and migration. Autophagy is a self-degradative process that, providing energy sources, removing damaged organelles and misfolded or aggregated proteins, allows cell survival in stress conditions or, when iper-activated, leads to non-apoptotic programmed cell death. Autophagy is often deregulated in cancer cells in which plays an important and complex role, being mainly oncogenic during cancer initiation, and tumor-suppressive during cancer progression. Studying the effects of HMGA1 knock-down in skin cancer cells SCC-13, I have found that it increases autophagy, as assessed by both western blot and immunofluorescence analysis of several autophagic markers, such as pS6, LC3 and SQSTM1/p62. Interestingly, the ability of HMGA1 depletion to increase autophagy is not restricted to skin cancer cells, since similar results have been achieved also silencing HMGA1 expression in HeLa cells, and mouse embryonic fibroblasts null for Hmga1 are more susceptible than the wild-type counterpart to undergo autophagy after starvation or treatment with rapamycin. Consistently, silencing of HMGA1 upregulates the two autophagy-initiating kinases Unc-51-like kinase 1 (ULK1) and Unc-51-like kinase 2 (ULK2), and functional experiments demonstrate that HMGA1 binds their promoter regions and negatively regulates their transcription. Accordingly, the block of ULK1 expression reduces the pro-autophagic effects induced by HMGA1 silencing indicating that they are, at least in part, mediated by ULK1. Taken together, these results clearly indicate that HMGA1 protects cancer cells from autophagy, thus suggesting, on one hand, a new mechanism through which HMGA1 can contribute to cancer progression and, on the other hand, a mechanism through which autophagy can be deregulated in cancer cells.

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