Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα
Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα
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DOI：
10.1038/s41418-023-01139-8
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发表时间：
2023-03-09
影响因子：
12.4
通讯作者：
Hu, Jiong
中科院分区：
文献类型：
--
作者：
Dai, Bo;Wang, Feng;Hu, Jiong
急性早幼粒细胞白血病（APL）是由癌蛋白PML-RAR α驱动的，其招募包括组蛋白去乙酰化酶（hdac）在内的辅抑制因子复合物，抑制细胞分化并促进APL的启动。全反式维甲酸（ATRA）联合三氧化二砷（ATO）或化疗可显著改善APL患者的预后。然而，ATRA和ATO可能出现难治性，这导致一组患者疾病复发。在这里，我们报道了HDAC3在AML APL亚型中高表达，并且HDAC3的蛋白水平与PML-RAR α呈正相关。在机制上，我们发现HDAC3在赖氨酸394处使PML-RAR α去乙酰化，从而减少pias1介导的PML-RAR α summoylation和随后rnf4诱导的泛素化。HDAC3抑制促进PML-RAR α泛素化和降解，降低PML-RAR α在野生型和ATRA或ato耐药APL细胞中的表达。此外，遗传或药理抑制HDAC3诱导APL细胞分化、凋亡和细胞自我更新减少，包括来自耐药APL患者的原发性白血病细胞。使用细胞系和患者来源的异种移植模型，我们证明使用HDAC3抑制剂或ATRA/ATO联合治疗可减少APL进展。总之，我们的研究通过去乙酰化PML-RAR α确定了HDAC3作为PML-RAR α癌蛋白的正调节因子的作用，并提示靶向HDAC3可能是治疗复发/难治性APL的一种有希望的策略。
Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RAR alpha, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RAR alpha. Mechanistically, we found that HDAC3 deacetylated PML-RAR alpha at lysine 394, which reduced PIAS1-mediated PML-RAR alpha SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RAR alpha ubiquitylation and degradation and reduced the expression of PML-RAR alpha in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RAR alpha oncoprotein by deacetylating PML-RAR alpha and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.