Biology subjects

Magalhaes, Y. T.

Publications and source records attributed to Magalhaes, Y. T..

4 recordsLinked to original sources

bioRxiv2026

DUSP12 regulates NAT10-mediated RNA acetylation to modulate DNA repair and therapeutic response in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer arising from hepatocytes, is an aggressive hepatic malignancy with limited therapeutic options and poor prognosis. Chemotherapy remains an important treatment for advanced disease, though the mechanisms influencing drug sensitivity remain elusive. This study investigates the role of dual-specificity phosphatase 12 (DUSP12) and its interaction with the nucleolar protein NAT10 in the hepatic cellular response to genotoxic stress. We demonstrate that doxorubicin (DX) induces superior cytotoxicity over cisplatin in hepatocellular carcinoma models, associated with a stronger DNA damage response (DDR), nucleolar stress, and delocalization of NAT10 from the nucleolus to the nucleoplasm, where it colocalized with DUSP12. Genetic ablation of DUSP12 sensitized cells to DX, increasing DNA damage markers (p53, p-p53(Ser15), {gamma}H2AX(Ser139)) and delaying the repair of DNA strand breaks. DUSP12 knockout also caused redistribution of nucleolar proteins NAT10 and TCOF1. Pharmacological inhibition of NAT10 in DUSP12-deficient cells further enhanced DX sensitivity, revealing a synthetic-lethal interaction. We identified a direct association between NAT10 and DUSP12s functional domains, with evidence indicating NAT10 is a DUSP12 substrate. Consequently, DUSP12 knockout elevated NAT10 phosphotyrosine levels and reduced ac4C RNA acetylation, indicating functional impairment of NAT10. Corroborating these findings, patient data showed frequent DUSP12 amplification in HCC, correlating with poor survival and enrichment in DDR and ribosome biogenesis pathways. Our results establish the DUSP12-NAT10-ac4C axis as a molecular link between the DDR and nucleolar stress, highlighting previously unrecognized therapeutic vulnerability in HCC.

cancer biology↗

bioRxiv2024

Acquisition and reversal of glioblastoma chemoresistance are mediated by the Rho GTPase pathway

Glioblastoma (GBM) are highly aggressive tumors treated mainly with surgery, radiotherapy, and chemotherapy. Innovative multimodal therapies are needed, targeting the immune system, tumor metabolism, and cell signaling. Our research focuses on the role of the actin cytoskeleton and Rho GTPases in modulating DNA damage repair and therapeutic sensitivity in GBM cells. We developed GBM sublines resistant to temozolomide (TMZ) and cisplatin (CP), and assessed actin stress fiber organization, Rho pathway activity, and resistance phenotype. TMZ-resistant clones exhibited increased Rho pathway activity, elevated p53 and DNA double-strand break (DSB) repair pathways, but reduced MMR protein levels. Importantly, Rho GTPase inhibition restored TMZ-resistant clones sensitivity to TMZ and CP, counteracting chemoresistance. While both drugs reduced DNA repair capacity in normal GBM cells--exacerbated by Rho inhibition--TMZ-resistant clones with overactivated Rho pathways did not show this effect. This response was p53-wild-type dependent, as p53-mutant GBM cells were unresponsive to Rho inhibition. However, p53-mutant cells treated with PRIMA-1 showed restored sensitivity to chemotherapeutics with Rho inhibition. Furthermore, modulation of the actin cytoskeleton and Rho GTPases affected sensitivity and viability in GBM spheroid models exposed to chemotherapy. In summary, Rho pathway activity and actin cytoskeleton dynamics are critical for both the development and reversal of chemoresistance in GBM tumors. STATEMENT OF SIGNIFICANCEChemoresistance in glioblastomas modulates the Rho GTPases pathway and actin cytoskeleton, while negatively affecting DNA repair. Downmodulating the actin circuitry in resistant GBMs sensitizes them to TMZ and CP drugs.

cancer biology↗

bioRxiv2024

Dual Specificity Phosphatase 3 knockdown drives myeloid leukemia cells to differentiate into macrophages and polarize

The dual-specificity phosphatase 3 (DUSP3) has been implicated in the maintenance of genomic stability, cell cycle, proliferation, and differentiation. Recently we reported an important role of the interaction between DUSP3 and nucleophosmin (NPM) proteins on the regulation of the p53 actions to maintain genomic stability. Since both p53 and NPM often have mutations related to a diverse set of leukemia, this work aimed to evaluate the roles of DUSP3 in the differentiation of two acute myeloid leukemia cell lines not expressing the p53 protein, and the potential correlations with NPM expression. The results demonstrated higher levels of DUSP3 in THP-1 cells compared to HL-60 cells under basal conditions. After PMA-induced differentiation into macrophages, only HL-60 cells presented a dramatic decrease in DUSP3 and NPM proteins expression. The permanent DUSP3 knockdown in THP-1 and HL-60 cells contributed to their differentiation and non-classical polarization after PMA exposure, since the CD14, MHCII, and CD163 markers were decreased whereas the CD11b and CD206 markers were increased. Bioinformatics analyses identified that the negative regulation of the npm1 and dusp3 genes correlates with the reduced survival of patients with acute myeloid leukemia (AML) and the strong positive correlation existing between the expression of these two genes is progressively lost according to the degree of maturation of the myeloid cells. These results suggest DUSP3 plays regulatory roles of differentiation and polarization of myeloid cells, and its association with NPM expression levels may allow a better understanding of mechanisms involved in leukemia and treatment resistance. HIGHLIGHTSDUSP3 knockdown drives myeloid leukemia cells to differentiation DUSP3 silencing drives myeloid leukemia cells to macrophage polarization DUSP3 and NPM association are potential targets for leukemia treatment and resistance

immunology↗

bioRxiv2023

Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis

Mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in tissue-resident CD11c+ myeloid cells (CD11cRic{Delta}/{Delta}), this study investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon DSS-induced colitis, lack of mTORC2 signaling CD11c+ cells diminish colonic inflammation, abrogates dendritic cell (DC) migration to the mesenteric lymph nodes (MLN), thereby diminishing the infiltration of T helper (Th) 17 cells in the lamina propria (LP). These findings corroborate with abrogation of cytoskeleton organization and decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis (UC) patients revealed increased gene expression of pro-inflammatory cytokines which coincided with augmented expression of mTOR pathway, positive correlation between the DC marker ITGAX, and IL-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses and this way, ameliorates the progression and severity of intestinal inflammatory diseases.

immunology↗