The overexpression of HMGA proteins plays a pivotal role in neoplastic transformation and is responsible for aggressive tumor phenotypes, characterized by enhanced metastatic potential and resistance to chemotherapy. Notably, HMGA1 has been identified as a key regulator of cancer stem cell self-renewal, which is crucial for tumor initiation, maintenance, therapeutic resistance, and recurrence. Several studies, including our own, have demonstrated that HMGA1 overexpression contribute to resistance against multiple chemotherapeutic agents, including cetuximab. Consequently, HMGA proteins represent promising targets for novel cancer therapies.

To identify potential inhibitors of HMGA protein function, we conducted high-throughput screening analyses using two libraries of molecules: the Sigma LOPAC 1280 and the Prestwick Chemical Library 1280. Electrophoretic mobility shift assays (EMSA) were subsequently performed to assess the ability of the selected molecules to displace HMGA proteins from their target DNA sequences and to inhibit HMGA binding to target proteins in vitro. Functional assays were conducted on breast and colon cancer cell lines, with or without HMGA1 expression, to evaluate the specificity and efficacy of the identified inhibitors.

Our screening identified seven molecules capable of interacting with HMGA proteins. EMSA experiments revealed that some of these compounds effectively disrupted HMGA-DNA interactions and inhibited HMGA binding to its target proteins in vitro. Functional assay further demonstrated that two of these molecules, tannic acid and benserazide, selectively inhibited HMGA function in breast and colon cancer cells, and reduced their aggressive phenotype, including high proliferation rate and stem cell potential.

These findings highlight the possibility of targeting HMGA proteins as a novel strategy to overcome chemo-resistance in aggressive cancers.