HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis
HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis
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HMGCS1通过内质网-UPR-线粒体轴驱动急性髓系白血病的耐药性
DOI：
10.1016/j.biopha.2021.111378
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hui Zeng
中科院分区：
文献类型：
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作者：
Cheng Zhou;Jue Li;Juan Du;Xinya Jiang;Xuejun Xu;Yi Liu;Qun He;Liang Hui;Peng Fang;Huien Zhan;Hui Zeng
羟-3-甲基戊二酰辅酶a合成酶1 （HMGCS1）是胆固醇合成甲戊酸途径的关键酶。HMGCS1表达异常在许多实体瘤中都很常见。它也被发现在新诊断（ND）和复发/难治性（RR）急性髓性白血病（AML）患者中过表达。既往研究证实HMGCS1可诱导AML细胞耐药。然而，HMGCS1促进化学耐药的潜在机制尚不清楚。在这里，我们证实HMGCS1抑制剂Hymeglusin增强了AML细胞系中阿霉素/阿霉素（Ara-c/ADR）的化学敏感性。此外，耐Ara-c的HL-60细胞（HL-60/Ara-c）和耐ADR的HL-60细胞（HL-60/ADR）对HMGCS1抑制的敏感性高于HL-60细胞。此外，我们证明转录因子GATA1是HMGCS1的上游调控因子，可以直接结合HMGCS1启动子。与AML-CR组相比，Tunicamycin （Tm）治疗后AML-RR患者骨髓细胞线粒体数量增加，内质网（ER）损伤减轻。HMGCS1在内质网应激下保护线粒体和内质网，上调AML细胞中展开蛋白反应（UPR）下游分子。综上所述，我们证明HMGCS1可以上调UPR下游成分，保护线粒体和内质网免受应激下AML细胞的损伤，从而赋予耐药性。因此，HMGCS1可作为治疗化疗不耐受患者和AML-RR患者的新靶点。
Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.