Chouhan Surbhi, Muhammad Naoshad, Usmani Darksha, Khan Tabish H, Kumar Anil
Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Cecil H and Ida Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Int J Mol Sci. 2024 Dec 28;26(1):183. doi: 10.3390/ijms26010183.
Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context. It reveals their multifaceted impact on hallmark cancer processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, resisting cell death, inducing angiogenesis, and enabling replicative immortality. SIRT1, for example, fosters chemoresistance and castration-resistant prostate cancer through metabolic reprogramming, immune modulation, androgen receptor signaling, and enhanced DNA repair. SIRT3 and SIRT4 suppress oncogenic pathways by regulating cancer metabolism, while SIRT2 and SIRT6 influence tumor aggressiveness and androgen receptor sensitivity, with SIRT6 promoting metastatic potential. Notably, SIRT5 oscillates between oncogenic and tumor-suppressive roles by regulating key metabolic enzymes; whereas, SIRT7 drives PCa proliferation and metabolic stress adaptation through its chromatin and nucleolar regulatory functions. Furthermore, we provide a comprehensive summary of the roles of individual sirtuins, highlighting their potential as biomarkers in PCa and exploring their therapeutic implications. By examining each of these specific mechanisms through which sirtuins impact PCa, this review underscores the potential of sirtuin modulation to address gaps in managing advanced PCa. Understanding sirtuins' regulatory effects could redefine therapeutic approaches, promoting precision strategies that enhance treatment efficacy and improve outcomes for patients with aggressive disease.
前列腺癌（PCa）仍然是一项严峻的全球健康挑战，死亡率高且具有显著的异质性，尤其是在晚期阶段。虽然早期PCa通常可以通过传统治疗进行控制，但转移性PCa却具有众所周知的耐药性，这凸显了对精确生物标志物和创新治疗策略的迫切需求。本综述聚焦于沉默调节蛋白（一类依赖烟酰胺腺嘌呤二核苷酸的组蛋白脱乙酰酶）的双重作用，剖析它们在不同细胞环境下对PCa肿瘤抑制或进展的独特贡献。研究揭示了它们对癌症标志性进程的多方面影响，包括维持增殖信号、逃避生长抑制、激活侵袭和转移、抵抗细胞死亡、诱导血管生成以及实现复制永生。例如，SIRT1通过代谢重编程、免疫调节、雄激素受体信号传导和增强DNA修复促进化疗耐药性和去势抵抗性前列腺癌。SIRT3和SIRT4通过调节癌症代谢抑制致癌途径，而SIRT2和SIRT6影响肿瘤侵袭性和雄激素受体敏感性，其中SIRT6促进转移潜能。值得注意的是，SIRT5通过调节关键代谢酶在致癌和肿瘤抑制作用之间振荡；而SIRT7通过其染色质和核仁调节功能驱动PCa增殖和代谢应激适应。此外，我们全面总结了各个沉默调节蛋白的作用，强调它们作为PCa生物标志物的潜力，并探讨它们的治疗意义。通过研究沉默调节蛋白影响PCa的每一种具体机制，本综述强调了调节沉默调节蛋白在填补晚期PCa管理空白方面的潜力。了解沉默调节蛋白的调节作用可能会重新定义治疗方法，促进精准策略，提高治疗效果，改善侵袭性疾病患者的预后。
