Novel Cell-Penetrating Peptides Derived From Scaffold-Attachment- Factor A Inhibits Cancer Cell Proliferation and Survival.

Pavan Kumar Puvvula,Anne M Moon

doi:10.3389/fonc.2021.621825

Abstract

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.

Highlights

Scaffold-attachment-factor A (SAFA, called hnRNPU) belongs to the hnRNP family of proteins and functions in diverse processes such as epigenetic regulation, transcription, alternative splicing, translation, and mRNA stability [1,2,3,4]
SAFA is a multimodular protein involved in the structural organization of nuclear matrix [42], genome integrity [84], transcription regulation [8], alternative splicing [3], and mRNA stability [11]
Mechanistic understanding of SAFA in cancer cell behavior is still primitive and it has not been probed as a therapeutic target

Summary

Introduction

Scaffold-attachment-factor A (SAFA, called hnRNPU) belongs to the hnRNP family of proteins and functions in diverse processes such as epigenetic regulation, transcription, alternative splicing, translation, and mRNA stability [1,2,3,4]. SAFA-mediated transcriptional activation and repression are the result of its association with p300 [5] and CBX5 [6], respectively. SAFA participates in transcription by directly associating with BRG1 complex [7] and/or with core-TFIIH complex [8]. It plays a structural role in nuclear organization by selectively tethering chromatin loops to the nuclear matrix [9, 10]. SAFA binds to both coding and non-coding transcripts and functions as a global splicing regulator [3] and enhances the stability of some transcripts by binding to their 3′ UTR [11]. In X-chromosome inactivation, the RGG domain mediates recruitment and layering of the Xist molecule on the X-chromosome [15, 16]

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Conclusion