Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies

Pegoraro, Silvia; Ros, Gloria; Sgubin, Michela; Petrosino, Sara; Zambelli, Alberto; Sgarra, Riccardo; Manfioletti, Guidalberto

doi:10.1080/14728222.2020.1814738

Cited by 9 publications

(13 citation statements)

References 184 publications

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“…Yet, by inducing the expression of key genes involved in the plasminogen activation system, such as SERPINE1 and PLAU, HMGA1 modulates the TNBC cell secretome and thus stimulates TNBC cell migration in an autocrine way [59]. However, although HMGA1 has been suggested as a potential target in breast cancer [60], the regulatory mechanisms of this factor in the specific context of TNBC pathophenotype remain largely unclear.…”

Section: Discussionmentioning

confidence: 99%

Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer

et al. 2021

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Among breast cancer subtypes, triple‐negative breast cancer (TNBC) is the most aggressive with the worst prognosis and the highest rates of metastatic disease. To identify TNBC gene signatures, we applied the network‐based methodology implemented by the SWIM software to gene expression data of TNBC patients in The Cancer Genome Atlas (TCGA) database. SWIM enables to predict key (switch) genes within the co‐expression network, whose perturbations in expression pattern and abundance may contribute to the (patho)biological phenotype. Here, SWIM analysis revealed an interesting interplay between the genes encoding the transcription factors HMGA1, FOXM1, and MYBL2, suggesting a potential cooperation among these three switch genes in TNBC development. The correlative nature of this interplay in TNBC was assessed by in vitro experiments, demonstrating how they may actually modulate the expression of each other.

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Section: Discussionmentioning

confidence: 99%

Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer

et al. 2021

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“…Silencing of HMGA1 impairs cancer stem self-renewal, migration, and invasiveness. Consistently, depletion of HMGA1 reduces the metastatic ability in vivo . , Another reason to consider HMGA proteins as potential molecular targets is that HMGA1 expression generally increases chemo- and radio-resistance in almost all cancers studied, as recently reviewed …”

Section: Introductionmentioning

confidence: 85%

“…16,17 Another reason to consider HMGA proteins as potential molecular targets is that HMGA1 expression generally increases chemoand radio-resistance in almost all cancers studied, as recently reviewed. 15 All these considerations have led over the years to exploit different strategies to target HMGA, trying to counteract their activities (reviewed in ref 15). Minor groove binders (MGBs), small molecules capable of binding DNA in the minor groove especially in AT-rich regions, have been investigated to this end.…”

Section: ■ Introductionmentioning

confidence: 99%

Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity

Mori,

Ghirga,

Amato

et al. 2023

ACS Omega

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HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the DNA minor groove of AT-rich stretches. HMGA are functionally involved in regulating transcription, RNA processing, DNA repair, and chromatin remodeling and dynamics. These proteins are highly expressed and play essential functions during embryonic development. They are almost undetectable in adult tissues but are re-expressed at high levels in all cancers where they are involved in neoplastic transformation and cancer progression. We focused on identifying new small molecules capable of binding into the minor groove of AT-rich DNA sequences that could compete with HMGA for DNA binding and, thus, potentially interfere with their activities. Here, a docking-based virtual screening of a unique high diversity in-house library composed of around 1000 individual natural products identified 16 natural compounds as potential minor groove binders that could inhibit the interaction between HMGA and DNA. To verify the ability of these selected compounds to compete with HMGA proteins, we screened them using electrophoretic mobility shift assays. We identified Sorocein C, a Diels–Alder (D–A)-type adducts, isolated from Sorocea ilicifolia and Sorocea bonplandii with an HMGA/DNA-displacing activity and compared its activity with that of two structurally related compounds, Sorocein A and Sorocein B. All these compounds showed a cytotoxicity effect on cancer cells, suggesting that the Sorocein-structural family may provide new and yet unexplored chemotypes for the development of minor groove binders to be evaluated as anticancer agents.

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“…HMGA1 is defined as an oncofetal protein since it is highly expressed during embryogenesis, its expression decreases to very low levels or it is absent in adults but then it is overexpressed in a variety of tumours [ 10 ]. Indeed, several works demonstrated that HMGA1 expression is correlated with high tumour grade and metastasis formation, resistance to therapies and poor prognosis in a large set of human malignant neoplasias, and it is directly involved in the development and progression of cancer [ 1 , 11 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…HMGA1 has been investigated in breast cancer (BC) and in particular in the triple-negative subtype (TNBC) [ 1 , 11 , 17 ]. A causal role of HMGA1 in BC onset and development has been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel

et al. 2022

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High Mobility Group A1 (HMGA1) is an architectural chromatin factor involved in the regulation of gene expression and a master regulator in Triple Negative Breast Cancer (TNBC). In TNBC, HMGA1 is overexpressed and coordinates a gene network that controls cellular processes involved in tumour development, progression, and metastasis formation. Here, we find that the expression of HMGA1 and of the microtubule-destabilizing protein stathmin correlates in breast cancer (BC) patients. We demonstrate that HMGA1 depletion leads to a downregulation of stathmin expression and activity on microtubules resulting in decreased TNBC cell motility. We show that this pathway is mediated by the cyclin-dependent kinase inhibitor p27kip1 (p27). Indeed, the silencing of HMGA1 expression in TNBC cells results both in an increased p27 protein stability and p27-stathmin binding. When the expression of both HMGA1 and p27 is silenced, we observe a significant rescue in cell motility. These data, obtained in cellular models, were validated in BC patients. In fact, we find that patients with high levels of both HMGA1 and stathmin and low levels of p27 have a statistically significant lower survival probability in terms of relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with respect to the patient group with low HMGA1, low stathmin, and high p27 expression levels. Finally, we show in an in vivo xenograft model that depletion of HMGA1 chemo-sensitizes tumour cells to paclitaxel, a drug that is commonly used in TNBC treatments. This study unveils a new interaction among HMGA1, p27, and stathmin that is critical in BC cell migration. Moreover, our data suggest that taxol-based treatments may be more effective in reducing the tumour burden when tumour cells express low levels of HMGA1.

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Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies

Cited by 9 publications

References 184 publications

Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer

Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer

Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity

HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel

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