Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4⁺ T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.

皮肤T细胞淋巴瘤（CTCL）代表非霍奇金淋巴瘤的一种罕见形式，其特征是恶性CD4 ⁺ T细胞在皮肤中积累。TP53遗传变异是CTCL中最普遍的遗传异常之一。因此，它是创新治疗方法的有希望的目标。我们发现p53可以与组蛋白脱乙酰基酶（HDAC）1和HDAC8进行物理相互作用，随后被脱乙酰基化，从而在CTCL细胞中失去其功能，并且p53下游凋亡相关基因被阻遏。因此，HDAC抑制剂显示的抗CTCL活性取决于p53状态。但是，最近的研究报道，HDAC抑制剂可通过调节ATP结合盒转运蛋白在癌细胞中诱导多种耐药性。此外，我们发现天然黄e素对HDAC1和HDAC8表现出抑制作用。尽管HDAC1的抑制作用很轻微，黄ical素可通过泛素蛋白酶体途径诱导HDAC1降解，从而显着上调组蛋白H3的乙酰化而不会促进ATP结合盒转运蛋白基因的表达。在机理上，黄ical苷在CTCL中显示出比传统的HDAC抑制剂更好的生长抑制作用。这项研究表明T细胞淋巴瘤细胞中HDAC1，HDAC8和p53的特殊机制，并确定了潜在且安全的天然HDAC抑制剂用于CTCL的治疗。