Puvvula Pavan Kumar, Buczkowski Stephanie, Moon Anne M
Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Clinic, Danville, PA, USA.
Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Mol Ther Oncolytics. 2021 Oct 19;23:342-354. doi: 10.1016/j.omto.2021.10.004. eCollection 2021 Dec 17.
hnRNPK is a multifunctional protein that plays an important role in cancer cell proliferation and metastasis via its RNA- and DNA-binding properties. Previously we showed that cell-penetrating peptides derived from the RGG RNA-binding domain of SAFA (hnRNPU) disrupt cancer cell proliferation and survival. Here we explore the efficacy of a peptide derived from the RGG domain of hnRNPK. This peptide acts in a dominant-negative manner on several hnRNPK functions to induce death of multiple types of cancer cells. The peptide phenocopies the effect of hnRNPK knockdown on its mRNA-stability targets such as and and alters the levels and locations of long non-coding RNAs (lncRNAs) and proteins required for nuclear and paraspeckle formation and function. The RGG-derived peptide also decreases euchromatin as evidenced by loss of active marks and polymerase II occupancy. Our findings reveal the potential therapeutic utility of the hnRNPK RGG-derived peptide in a range of cancers.
异质性核糖核蛋白K（hnRNPK）是一种多功能蛋白，通过其RNA结合和DNA结合特性在癌细胞增殖和转移中发挥重要作用。此前我们发现，源自SAFA（异质性核糖核蛋白U，hnRNPU）的RGG RNA结合结构域的细胞穿透肽可破坏癌细胞的增殖和存活。在此，我们探究源自hnRNPK的RGG结构域的一种肽的功效。该肽以显性负性方式作用于hnRNPK的多种功能，从而诱导多种类型癌细胞死亡。该肽模拟了hnRNPK敲低对其mRNA稳定性靶点（如 和 ）的影响，并改变了核仁旁斑形成和功能所需的长链非编码RNA（lncRNA）和蛋白质的水平及定位。RGG衍生肽还会导致常染色质减少，这可通过活性标记的丧失和聚合酶II的占据情况得到证明。我们的研究结果揭示了hnRNPK RGG衍生肽在一系列癌症中的潜在治疗效用。
