hnRNPK-derived cell-penetratingpeptide inhibits cancer cell survival

Pavan Kumar Puvvula; Stephanie Buczkowski; Anne M Moon

doi:10.1016/j.omto.2021.10.004

hnRNPK-derived cell-penetratingpeptide inhibits cancer cell survival

Mol Ther Oncolytics. 2021 Oct 19:23:342-354. doi: 10.1016/j.omto.2021.10.004. eCollection 2021 Dec 17.

Authors

Pavan Kumar Puvvula¹, Stephanie Buczkowski¹, Anne M Moon^{1

2

3}

Affiliations

¹ Department of Molecular and Functional Genomics, Weis Center for Research, Geisinger Clinic, Danville, PA, USA.
² Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
³ The Mindich Child Health and Development Institute, Hess Center for Science and Medicine at Mount Sinai, New York, NY, USA.

Abstract

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 KLF4 and EGR1 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.

Keywords: RNA processing; cancer therapy; cell-penetrating peptides; chromatin marks; dominant-negative; hnRNPK; lncRNA; nuclear paraspeckles; nuclear speckles.