Puvvula Pavan Kumar, Moon Anne M
Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Clinic, Danville, PA, United States.
Department of Human Genetics, University of Utah, Salt Lake City, UT, United States.
Front Oncol. 2021 Mar 30;11:621825. doi: 10.3389/fonc.2021.621825. eCollection 2021.
Scaffold-attachment-factor A (SAFA) has important roles in many normal and pathologic cellular processes but the scope of its function in cancer cells is unknown. Here, we report dominant-negative activity of novel peptides derived from the SAP and RGG-domains of SAFA and their effects on proliferation, survival and the epigenetic landscape in a range of cancer cell types. The RGG-derived peptide dysregulates SAFA binding and regulation of alternatively spliced targets and decreases levels of key spliceosome proteins in a cell-type specific manner. In contrast, the SAP-derived peptide reduces active histone marks, promotes chromatin compaction, and activates the DNA damage response and cell death in a subset of cancer cell types. Our findings reveal an unprecedented function of SAFA-derived peptides in regulating diverse SAFA molecular functions as a tumor suppressive mechanism and demonstrate the potential therapeutic utility of SAFA-peptides in a wide range of cancer cells.
支架附着因子A（SAFA）在许多正常和病理细胞过程中发挥重要作用，但其在癌细胞中的功能范围尚不清楚。在此，我们报告了源自SAFA的SAP和RGG结构域的新型肽的显性负性活性及其对一系列癌细胞类型的增殖、存活和表观遗传格局的影响。源自RGG的肽以细胞类型特异性方式失调SAFA结合和对可变剪接靶标的调节，并降低关键剪接体蛋白的水平。相比之下，源自SAP的肽减少活性组蛋白标记，促进染色质压实，并在一部分癌细胞类型中激活DNA损伤反应和细胞死亡。我们的研究结果揭示了SAFA衍生肽在调节多种SAFA分子功能作为肿瘤抑制机制方面前所未有的功能，并证明了SAFA肽在广泛癌细胞中的潜在治疗效用。
