Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation

A recently developed synthetic retinoid abrogates proliferation and induces apoptosis of drug‐resistant malignant‐cancer‐stem‐cell‐like cells. However, the underlying mechanisms of how the synthetic retinoid induces cancer‐stem‐cell‐like cell tumor‐repopulating cell (TRC) apoptosis are elusive. Here, it is shown that although the retinoid and conventional anticancer drugs cisplatin, all‐trans retinoic acid, and tazarotene all inhibit cytoskeletal tension and decondense chromatin prior to inducing TRC apoptosis, half‐maximal inhibitory concentration of the retinoid is 20‐fold lower than those anticancer drugs. The synthetic retinoid induces retinoic acid receptor gamma (RARγ) translocation from the nucleus to the cytoplasm, leading to reduced RARγ binding to Cdc42 promoter and Cdc42 downregulation, which decreases filamentous‐actin (F‐actin) and inhibits cytoskeletal tension. Elevating F‐actin or upregulating histone 3 lysine 9 trimethylation decreases retinoid‐induced DNA damage and apoptosis of TRCs. The combinatorial treatment with a chromatin decondensation molecule and the retinoid inhibits tumor metastasis in mice more effectively than the synthetic retinoid alone. These findings suggest a strategy of lowering cell tension and decondensing chromatin to enhance DNA damage to abrogate metastasis of cancer‐stem‐cell‐like cells with high efficacy.