Facultad de Ciencias Biológicas

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Browsing Facultad de Ciencias Biológicas by Author "Álvarez Martínez-Conde, Claudia Isabel"

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    Regulación transcripcional de NUAK1 por SALL2 frente a estrés metabólico.
    (Universidad de Concepción, 2023) Álvarez Martínez-Conde, Claudia Isabel; Pincheira Barrera, Roxana Jacqueline; Castro Alma, Ariel Fernando
    Metabolic stress in cancer is critical for migration, invasion, and metastasis. NUAK1, a member of the AMPK-related kinases (ARKs) family, is deregulated in some types of cancer. NUAK1 overexpression promotes cell migration, metastasis, and survival in different contexts, including metabolic stress. Data from our labora-tory show that NUAK1 is transcriptionally induced by glucose deprivation; however, the mechanisms involved in this response are unknown. It has been proposed that SALL2, a transcription factor with dual roles in cancer, may be implicated. Although SALL2 generally acts as a tumor suppressor, under conditions of metabolic stress, its expression increases and contributes to cell survival in MEF cells; however, the mechanism by which SALL2 exerts this role has not been reported. Bioinformatic analyses were performed using databases such as miPanda and R2, which showed a positive correlation between SALL2 and NUAK1 levels in several tissues. According-ly, we found SALL2 dependence for the increase of NUAK1 expression against meta-bolic stress due to glucose deficiency. To determine whether NUAK1 is a direct target of SALL2, we analyzed the promoter of human NUAK1 and mouse Nuak1, in which we found consensus SALL2 binding sites conserved in both species. Through lucifer-ase reporter gene assays, we demonstrated that SALL2 gain-of-function increas-es Nuak1 promoter activity, while chromatin immunoprecipitation (ChIP) studies showed that SALL2 binds to the NUAK1 promoter. Controversial trends were found when testing the pro-survival role of SALL2 against metabolic stress in different mod-els. The SALL2-dependent increase in cell survival was only observed in loss-of-function models (silencing), similar to previous data using wild-type and SALL2-deficient MEF cells. Moreover, our results suggest a dependence on NUAK1 for the pro-survival role of SALL2. Interestingly, NUAK1 inhibition under high glucose conditions induced vacuole formation corresponding to the phenotype of a type of cell death known as methuosis, which is more abundant in shCtrl cells than silenced (shSall2) cells. These data are consistent with previous observations from the labora-tory in colon cancer cells, associating SALL2 with the generation of methuosis. Our data suggest NUAK1 as a transcriptional target of SALL2 associated with cell survival under metabolic stress by glucose deprivation. Elucidating the nor-mal mechanisms of transcriptional regulation of NUAK1 is essential to understanding its dysregulation in cancer.
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