SIRT1 Regulates RNA Stability to Promote Breast Cancer

SIRT1 调节 RNA 稳定性促进乳腺癌发生

• 批准号: 10529677
• 负责人: Fangyu Wang
• 金额: $ 4.47万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529677
• 关键词: 3' Untranslated Regions; Acetylation; Aging; Area; Binding; Biogenesis; Breast Cancer Cell; Cancer Biology; Cancer Cell Growth; Catalytic Domain; Cell Aging; Cell Survival; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Deacetylase; Development; Disease; Disease Progression; Down-Regulation; Ectopic Expression; Exonuclease; Extracellular Space; Goals; Grant; Hydrolase; Impairment; Laboratories; Lead; Learning; Longevity; Lysine; Lysosomes; Malignant Neoplasms; Mediating; Multivesicular Body; Neoplasm Metastasis; Pathway interactions; Patients; Persons; Phase; Play; Postdoctoral Fellow; Process; Production; Proteins; RNA; RNA Stability; RNA-Binding Proteins; Research; Research Personnel; Research Project Grants; Resistance; Risk Factors; Role; SIRT1 gene; Schools; Therapeutic; Time; Transcript; Tumor Suppressor Proteins; Woman; Work; aged; aggressive breast cancer; base; breast cancer progression; cancer cell; cell age; cell growth; exosome; expectation; extracellular vesicles; graduate student; insight; intercellular communication; interest; knock-down; malignant breast neoplasm; migration; new therapeutic target; novel; novel strategies; prevent; protein expression; recruit; senescence; skills; small hairpin RNA; trafficking; trait; transcriptome sequencing; tumor growth; tumor progression; vacuolar H+-ATPase

Project Summary Breast cancer is responsible for the deaths of more than 600,000 women each year. Thus, there is an over- riding need to better understand the mechanisms that promote breast cancer, as this information can potentially lead to new strategies to treat the disease. Recently, the Cerione lab discovered a mechanism through which highly aggressive forms of breast cancer cells produce a secretome containing factors that promote cancer cell survival and metastatic spread. Specifically, the researchers showed that the decreased expression of the NAD+- dependent deacetylase Sirtuin 1 (SIRT1) increases the formation and release of exosomes, a specific class of extracellular vesicles (EVs) that are derived from multi-vesicular bodies (MVBs) within the endocytic/lysosomal trafficking pathway. This effect was due to the increased acetylation of the RNA binding protein, IGF2BP2, that binds to the 3' untranslated region of the transcript encoding ATP6V1A, a major catalytic subunit of the vacuolar ATPase (v-ATPase) that maintains the proper pH and activity of lysosomes. Acetylated IGF2BP2 recruits an exonuclease, XRN2, which degrades the ATP6V1A transcript, resulting in impaired lysosomal activity. Thus, MVBs that would otherwise be targeted and degraded in lysosomes are instead directed to the cell surface where they fuse with the plasma membrane and release their contents, i.e., exosomes enriched in unique cargo and soluble hydrolases, into the extracellular space. These components of the secretome were shown to work together to strongly promote the invasiveness of breast cancer cells. Whether there were additional transcripts that were regulated similarly to the ATP6V1A transcripts by SIRT1 and IGF2BP2 were then determined. Based on a comprehensive RNA sequencing analysis performed, fourteen transcripts were identified; four of which encode proteins that potentially play important roles in breast cancer progression and/or exosome biogenesis. For the F99 phase of this application, I plan to establish that the stability of these transcripts is indeed regulated by SIRT1 and IGF2BP2, and to investigate how changes in their levels impact breast cancer progression (Aim 1). In addition to the tumor suppressor role played by SIRT1 in breast cancer, reductions in its expression have also been heavily implicated in aging, a major risk factor for developing cancer, as well as other diseases. In the K00 phase of this proposal, I would like to investigate the interplay between aging and cancer. It has been recently shown that the accumulation of aged/senescent cells results in the production of a secretome that can increase the growth of cancer cells. My plan as a Post-doctoral trainee will be to determine whether the EVs from aged/senescent cells contribute to this effect. Furthermore, I am also interested in exploring whether the EVs secreted from cancer cells enable cells to evade undergoing senescence (Aim 2). Ultimately, the goal of this study is to understand the relationship between aging and cancer to help identify potential therapeutic treatment for patients.

项目摘要 乳腺癌每年造成60万以上女性死亡。因此，有一个过度的 骑行需要更好地了解促进乳腺癌的机制，因为这些信息可能会潜在 导致治疗疾病的新策略。最近，Cerione实验室发现了一种机制 高度侵略性的乳腺癌细胞产生的秘密组包含促进癌细胞的因素 生存和转移扩散。具体而言，研究人员表明NAD+ - 表达降低 依赖性脱乙酰基酶Sirtuin 1（SIRT1）增加了外泌体的形成和释放，这是一类特定类别 细胞外囊泡（EV），这些囊泡源自内吞/溶酶体内的多维体（MVB） 贩运途径。这种影响是由于RNA结合蛋白IGF2BP2的乙酰化增加所致 与编码ATP6V1A的转录本的3'未翻译区域结合，液泡的主要催化亚基 ATPase（V-ATPase）维持溶酶体的适当pH和活性。乙酰化的IGF2BP2招募 核酸酶XRN2降解ATP6V1A转录本，导致溶酶体活性受损。因此， 否则将靶向和降解在溶酶体中的MVB被指向细胞表面 他们与质膜融合并释放其内容物，即外泌体富含独特的货物和 可溶性水解酶进入细胞外空间。这些分泌组的这些成分被证明起作用 共同促进乳腺癌细胞的侵入性。是否还有其他成绩单 然后确定与ATP6V1A转录本相似的调节，然后确定IGF2BP2。基于 在进行的全面RNA测序分析中，确定了14个转录本。其中四个 编码潜在地在乳腺癌进展和/或外泌体生物发生中起重要作用的蛋白质。 对于此应用程序的F99阶段，我计划确定这些成绩单的稳定性确实受到调节 SIRT1和IGF2BP2，并研究其水平的变化如何影响乳腺癌的进展（AIM 1）。除了SIRT1在乳腺癌中扮演的肿瘤抑制作用外，其表达的降低还具有 也与衰老相关，这是癌症发展的主要危险因素以及其他疾病。在 该提案的K00阶段，我想研究衰老与癌症之间的相互作用。它一直 最近表明，老化/衰老细胞的积累会导致产生一个可分泌的人 增加癌细胞的生长。我作为博士后学员的计划将是确定电动汽车是否是否 从老化/衰老的细胞中有助于这种效果。此外，我也有兴趣探索 从癌细胞中分泌的电动汽车使细胞能够逃避经历衰老的（AIM 2）。最终，目标的目标 这项研究是了解衰老与癌症之间的关系，以帮助识别潜在的治疗性 患者的治疗。