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A Novel Screen for Expression Regulators of the Telomeric Protein TRF2 Identified Small Molecules That Impair TRF2 Dependent Immunosuppression and Tumor Growth.
Cancers (Basel), 13(12).
Telomeric repeat-binding factor 2 (TRF2) is a subunit of the shelterin proteincomplex, which binds to and protects telomeres from unwanted DNA damage response(DDR) activation. TRF2 expression plays a pivotal role in aging and cancer, beingdownregulated during cellular senescence and overexpressed during oncogenesis.Cancers overexpressing TRF2 often exhibit a poor prognosis. In cancer cells, TRF2plays multiple functions, including telomere protection and non-cell autonomousroles, promoting neo-angiogenesis and immunosuppression. We present here anoriginal screening strategy, which enables identification of small molecules thatdecrease or increase TRF2 expression. By screening a small library of Food andDrug Agency (FDA)-approved drugs, we identified two molecules (AR-A014418 andalexidine·2HCl) that impaired tumor growth, neo-angiogenesis andimmunosuppression by downregulating TRF2 expression in a mouse xenograft model.These results support the chemotherapeutic strategy of downregulating TRF2expression to treat aggressive human tumors and validate this cell-based assaycapable of screening for potential anti-cancer and anti-aging molecules bymodulating TRF2 expression levels.
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