Transcriptional Repression of SIRT3 Potentiates Mitochondrial Aconitase Activation to Drive Aggressive Prostate Cancer to the Bone.
Transcriptional Repression of SIRT3 Potentiates Mitochondrial Aconitase Activation to Drive Aggressive Prostate Cancer to the Bone.
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DOI：
10.1158/0008-5472.can-20-1708
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发表时间：
2021-01-01
期刊：
影响因子：
11.2
通讯作者：
Dasgupta S
中科院分区：
文献类型：
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作者：
Sawant Dessai A;Dominguez MP;Chen UI;Hasper J;Prechtl C;Yu C;Katsuta E;Dai T;Zhu B;Jung SY;Putluri N;Takabe K;Zhang XH;O'Malley BW;Dasgupta S
代谢失调是癌症进展的一个已知标志，然而促进代谢适应以驱动转移性癌症的致癌信号仍不清楚。在这里，我们发现雄激素受体(AR)及其辅助调节因子类固醇受体辅活化子(SRC-2)对线粒体脱乙酰基酶sirtuin3(SIRT3)的转录抑制增强了线粒体乌头酸酶(ACO2)的活性，有利于侵袭性前列腺癌的发生。ACO2促进线粒体柠檬酸合成以促进新生脂肪生成，ACO2的基因消融降低了总脂含量，并严重抑制了体内前列腺癌的进展。ACO2上的单个乙酰化标记lys258起调控基序的作用，而乙酰化缺陷的Lys258Arg突变体在酶活性上是无效的，无法挽救ACO2缺陷细胞的生长。ACO2的乙酰化受SIRT3可逆调节，SIRT3在包括前列腺癌在内的许多肿瘤中主要被抑制。机制上，SRC-2通过将组蛋白去乙酰化酶2(HDAC2)募集到SIRT3启动子上形成抑制性复合体，SRC-2的缺失增强了SIRT3的表达，同时降低了乙酰化ACO2。在人类前列腺癌中，ACO2活性显著升高，SRC-2的表达增加，SIRT3的表达降低，这是前列腺癌转移灶中丰富的遗传标志。在自发性骨转移的小鼠模型中，SRC-2的抑制重新激活了SIRT3的表达，并足以消除前列腺癌在骨微环境中的定植，这意味着这个核-线粒体调节轴是转移能力的决定因素。
Metabolic dysregulation is a known hallmark of cancer progression, yet the oncogenic signals that promote metabolic adaptations to drive metastatic cancer remain unclear. Here we show that transcriptional repression of mitochondrial deacetylase sirtuin 3 (SIRT3) by androgen receptor (AR) and its coregulator steroid receptor coactivator (SRC-2) enhances mitochondrial aconitase (ACO2) activity to favor aggressive prostate cancer. ACO2 promoted mitochondrial citrate synthesis to facilitate de novo lipogenesis, and genetic ablation of ACO2 reduced total lipid content and severely repressed in vivo prostate cancer progression. A single acetylation mark lysine258 on ACO2 functioned as a regulatory motif, and the acetylation-deficient Lys258Arg-mutant was enzymatically inactive and failed to rescue growth of ACO2-deficient cells. Acetylation of ACO2 was reversibly regulated by SIRT3, which was predominantly repressed in many tumors including prostate cancer. Mechanistically, SRC-2 bound AR formed a repressive complex by recruiting histone deacetylase 2 (HDAC2) to the SIRT3 promoter, and depletion of SRC-2 enhanced SIRT3 expression and simultaneously reduced acetylated-ACO2. In human prostate tumors, ACO2 activity was significantly elevated and increased expression of SRC-2 with concomitant reduction of SIRT3 was found to be a genetic hallmark enriched in prostate cancer metastatic lesions. In a mouse model of spontaneous bone metastasis, suppression of SRC-2 reactivated SIRT3 expression and was sufficient to abolish prostate cancer colonization in the bone microenvironment, implying this nuclear-mitochondrial regulatory axis is a determining factor for metastatic competence.