Suramin potently inhibits binding of the mammalian high mobility group protein AT-hook 2 to DNA

Abstract

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNAbinding protein which plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen high throughput screening (HTS) assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we discovered that suramin, a negatively charged antiparasitic drug potently inhibits the HMGA2-DNA interaction. Our results also show that the inhibition is through suramin binding to the AT-hooks of HMGA2, therefore blocking its DNA binding capacity. Furthermore, we demonstrate that suramin can induce brain tumor stem cells differentiation into cells with neurite-like structures, a process triggered by disrupting HMGA2-DNA interactions. Since suramin has strong antitumor and anti-metastasis activities, our discovery suggests that HMGA2 and HMGA2-like proteins may be the cellular target of this century-old drug.The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional nuclear protein associated with epithelial-to-mesenchymal transition (EMT) during embryonic development (1). Early studies showed that HMGA2 is related to preadipocyte proliferation and obesity (2-4). For example, Hmga2 knockout mice were severely deficient in fat cells and developed pygmy phenotype (5). The disruption of Hmga2 gene dramatically reduced obesity of leptin-deficient mice (Lep ob /Lep ob ) (2). These results suggest that HMGA2 is a potential target for the treatment of obesity. HMGA2 is also linked to oncogenesis. Its over and/or aberrant expression leads to the formation of a variety of tumors including benign tumors, such as lipomas (6), uterine leiomyomas (7), and fibroadenomas (8), and malignant tumors, such as lung cancer (9,10), breast cancer (11,12), prostate cancer (13), leukemia (14), and melanoma (15-18).Intriguingly, HMGA2 expression level always correlates with the degree of malignancy, metastasis, and a poor prognosis (19,20), suggesting that this protein is also a therapeutic target of anti-cancer and anti-metastasis drugs (21,22). Furthermore, HMGA2 is associated with neural and hematopoietic stem cell youth (23,24), human height (25), and human intelligence (26).HMGA2 is a small DNA-binding protein consisting of three "AT-hook" DNA binding motifs and a highly acidic C-terminal motif (27). These three "AT-hooks" contain a unique palindromic sequence, PGRGP, each side surrounded by one or two positively charged amino acids, i.e., Lysine or Arginine (28). HMGA2 is an intrinsically disordered protein (IDP (29)). When it binds to AT-rich DNA sequences, the "AT-hook" DNA binding motifs adopt defined structures (30).This disordered-to-ordered conformational transition allows HMGA2 to adapt to different ATrich DNA sequences and to participate in different nuclear activities, such as tra...

Engineered modular heterocyclic-diamidines for sequence-specific recognition of mixed AT/GC base pairs at the DNA minor groove

“…HOXA9 TF which play important roles in tumorigenesis, adipogenesis and acute myeloid leukemia. 18 The inhibition of protein-DNA binding in these systems was detected with a biosensor-surface plasmon resonance assay. 1 The ETS family is attractive for inhibitor development because many members of the family are well-characterized and have important functions in cell biology and human diseases.…”

Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin

“…(ii) Suramin and its analogues have been shown to inhibit Hpa in many human cancer cell lines [68][69][70][71]. (iii) Recently, it has been shown to bind HMGA2 and to potently inhibit DNA interactions, providing new insights into its anti-cancer and anti-metastasis functions, since the expression levels of HMGA proteins are associated with metastasis and poor prognosis for many cancer types [72].…”