SLX4IP Promotes Telomere Maintenance in Androgen Receptor-Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization.
SLX4IP Promotes Telomere Maintenance in Androgen Receptor-Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization.
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SLX4IP通过ALT样端粒PML定位促进雄激素受体非依赖性去势抵抗性前列腺癌的端粒维持
DOI：
10.1158/1541-7786.mcr-20-0314
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Taylor DJ
中科院分区：
文献类型：
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作者：
Mangosh TL;Awadallah WN;Grabowska MM;Taylor DJ
在晚期前列腺癌中，对雄激素剥夺疗法的抵抗是通过多种机制实现的，包括雄激素受体（AR）的丧失允许AR非依赖性生长。AR非依赖性去势抵抗性前列腺癌（CRPC）的治疗选择有限，定义生存的关键机制对于靶向这种致命疾病至关重要。我们的研究重点是确定CRPC采用的端粒维持机制（TMM）标志，以促进生存。端粒酶负责端粒延长以灌输复制永生并防止衰老，其中两种可用的TMM途径是端粒酶和端粒的替代延长（ALT）。在这里，我们发现AR非依赖性CRPC表现出非典型ALT样表型，具有可变的端粒酶表达和活性，而AR依赖性模型缺乏可辨别的ALT标志。此外，AR非依赖性CRPC细胞表现出SLX 4 IP水平升高，SLX 4 IP是一种参与促进ALT的蛋白质。SLX 4 IP在AR依赖性C4-2B细胞中的过表达促进ALT样表型和端粒维持。AR非依赖性DU 145和PC-3细胞中SLX 4 IP敲低导致ALT样标志物减少、端粒缩短和衰老诱导。在PC-3异种移植物中，这种作用转化为肿瘤体积减小。使用AR非依赖性进展的体外模型，AR依赖性C4-2B细胞中AR的丧失以SLX 4 IP依赖性方式促进非典型ALT样表型。SLX 4 IP表达不足减少了ALT样标志，并导致端粒丢失和衰老加速。这项研究证明了AR非依赖性CRPC对SLX 4 IP介导的ALT样标志的独特依赖性，这些标志的缺失诱导端粒缩短和衰老，从而损害复制永生。
In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. In addition, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induces telomere shortening and senescence, thereby impairing replicative immortality.