Regulation of HNRNP family by post-translational modifications in cancer

Abstract

Heterogeneous nuclear ribonucleoproteins (HNRNPs) represent a large family of RNA-binding proteins consisting of more than 20 members and have attracted great attention with their distinctive roles in cancer progression by regulating RNA splicing, transcription, and translation. Nevertheless, the cancer-specific modulation of HNRNPs has not been fully elucidated. The research of LC-MS/MS technology has documented that HNRNPs were widely and significantly targeted by different post-translational modifications (PTMs), which have emerged as core regulators in shaping protein functions and are involved in multiple physiological processes. Accumulating studies have highlighted that several PTMs are involved in the mechanisms of HNRNPs regulation in cancer and may be suitable therapeutic targets. In this review, we summarize the existing evidence describing how PTMs modulate HNRNPs functions on gene regulation and the involvement of their dysregulation in cancer, which will help shed insights on their clinical impacts as well as possible therapeutic tools targeting PTMs on HNRNPs.

Fig. 1. Types of PTMs (created with BioRender.com).

(1) classical modifications that are abundant in cells and play key roles in cellular energy metabolism, lipid metabolism, ketone body metabolism, and amino acid metabolism. (2) Modifications present only in cysteine. When cells are subjected to oxidative stress, oxidation modification on cysteine may occur as a response. (3) Membrane proteins glycosylation plays an important role in the protection, stability, and barrier of cell membranes. (4) Novel acylation modifications are involved in epigenetic regulation, which plays a role in DNA damage repair, histone acylation modification, chromatin packaging, and so on.

Fig. 2. Mechanisms of action of the HNRNP family in cancer (Created with BioRender.com).

The top of this picture represents the extracellular environment. From the top to bottom are the cell membrane, the cytoplasmic matrix, and the nucleus. At the bottom are the mechanisms affected by the HNRNPs. The proteins in purple are kinases or upstream regulatory enzymes, HNRNPs are in light blue, downstream transcripts are in gray, and the final mechanism is in black boxes. P Phosphorylation; AC Acetylation; Me Methylation; Ub Ubiquitination; SUMO Sumoylation.

Fig. 3. Overall summary of the regulation of HNRNPs by PTMs in cancer (created with BioRender.com).

As shown in this figure, the outer circle represents each cancer, and the inner circle is the PTMs type possessed by the HNRNPs corresponding to each cancer. On the right, we add an explanatory text to explain the abbreviations (P, Ub, Ac, Me, Sumo).