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. Additionally, 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. Implications: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induce telomere shortening and senescence, thereby impairing replicative immortality.

中文翻译：

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SLX4IP 通过类似 ALT 的端粒 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


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，从而实现不依赖于AR的生长。对于不依赖 AR 的去势抵抗性前列腺癌 (CRPC)，治疗选择有限，而定义对生存至关重要的机制对于针对这种致命疾病至关重要。我们的研究重点是确定 CRPC 为促进生存而采用的端粒维持机制 (TMM) 标志。 TMM 负责端粒延长，以实现复制永生并防止衰老，可用的两种 TMM 途径是端粒酶和端粒替代延长 (ALT)。在这里，我们发现 AR 独立的 CRPC 表现出非典型的 ALT 样表型，具有可变的端粒酶表达和活性，而 AR 依赖的模型缺乏可辨别的 ALT 特征。此外，不依赖 AR 的 CRPC 细胞表现出 SLX4IP 水平升高，SLX4IP 是一种与促进 ALT 相关的蛋白质。 AR 依赖性 C4-2B 细胞中 SLX4IP 过表达促进了 ALT 样表型和端粒维持。在不依赖 AR 的 DU145 和 PC-3 细胞中敲低 SLX4IP 会导致 ALT 样标志减少、端粒缩短和衰老诱导。在 PC-3 异种移植物中，这种效应转化为肿瘤体积的减小。使用 AR 独立进展的体外模型，AR 依赖性 C4-2B 细胞中 AR 的丧失以 SLX4IP 依赖​​性方式促进非典型 ALT 样表型。 SLX4IP 表达不足会减弱 ALT 样特征，并导致端粒丢失和衰老加速。 意义：这项研究表明，不依赖 AR 的 CRPC 对 SLX4IP 介导的 ALT 样标志具有独特的依赖性，这些标志的丧失会导致端粒缩短和衰老，从而损害复制永生性。