Drug-induced inhibition of HMGA and EZH2 activity as a possible therapy for anaplastic thyroid carcinoma

ABSTRACT

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal neoplasms in humans, and just limited progresses have been made to extend patient survival and decrease ATC-associated mortality. Thus, the identification of novel therapeutic strategies for treating ATC is needed. Recently, our group has identified two proteins with oncogenic activity, namely HMGA1 and EZH2, with pivotal roles in ATC cancer progression. Therefore, we tested the ability of trabectedin, a HMGA1-targeting drug, and GSK126, an inhibitor of EZH2 enzymatic activity, to impair cell viability of four ATC-derived cell lines. In the present study, we first confirmed the overexpression of HMGA1 and EZH2 in all ATC-derived cell lines and tissues compared to the normal primary thyroid cells and tissues. Then, treatment of the ATC cell lines with trabectedin and GSK126 resulted in a drastic induction of apoptotic cell death, which increased when the ATC cell lines were treated with a combination of both drugs. Conversely, normal primary human thyroid cells did not show any significant reduction in their viability when exposed to the same drugs. Noteworthy, both drugs induced the deregulation of EZH2- and HMGA1-controlled genes. Altogether, these findings propose the combination of trabectedin and GSK126 as possible novel strategy for ATC therapy.

KEYWORDS:

• HMGA
• EZH2
• Trabectedin
• GSK126
• anaplastic thyroid carcinoma

Acknowledgements

We thank Mrs. Giulia Speranza, Ms. Giuseppina Ippolito and Mrs. Mariarosaria Montagna from IEOS-CNR (Naples, Italy) for their technical support. This work was supported by Associazione Partenopea Ricerche Oncologiche (APRO).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Conceptualization, M.D.M., A.F. and F.E.; methodology, M.D.M., S.P., M.D.P., D.T., N.M.D.C, P.P., P.C., A.F. and F.E.; software, M.D.M., S.P., M.D.P., N.M.D.C, F.E.; validation, M.D.M., S.P., N.M.D.C. and F.E.; formal analysis, M.D.M., S.P., N.M.D.C., P.P. and F.E.; investigation, M.D.M., S.P. and F.E.; resources, M.D.P., D.T. and A.F.; data curation, M.D.M., S.P., M.D.P., D.T., N.M.D.C., P.P., P.C., A.F. and F.E.; writing-original draft preparation, M.D.M., S.P., M.D.P., D.T., N.M.D.C., P.P., P.C., A.F. and F.E.; writing – review and editing M.D.M., S.P., M.D.P., D.T., N.M.D.C., P.P., P.C., A.F. and F.E.; supervision, P.C, A.F. and F.E.; project administration, P.C., A.F. and F.E. All authors have read and agreed to the published version of the manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2023.2298027

Additional information

Funding

This research received no external funding