Noncoding RNA-encoded peptides in cancer: biological functions, posttranslational modifications and therapeutic potential

Abstract

In the present era, noncoding RNAs (ncRNAs) have become a subject of considerable scientific interest, with peptides encoded by ncRNAs representing a particularly promising avenue of investigation. The identification of ncRNA-encoded peptides in human cancers is increasing. These peptides regulate cancer progression through multiple molecular mechanisms. Here, we delineate the patterns of diverse ncRNA-encoded peptides and provide a synopsis of the methodologies employed for the identification of ncRNAs that possess the capacity to encode these peptides. Furthermore, we discuss the impacts of ncRNA-encoded peptides on the biological behavior of cancer cells and the underlying molecular mechanisms. In conclusion, we describe the prospects of ncRNA-encoded peptides in cancer and the challenges that need to be overcome.

Fig. 1

Identification of ncRNA-encoded peptides and their aberrant expression in various types of human primary tumors. Red arrows: Up-regulated. Green arrows: Down-regulated

Fig. 2

Identification of ncRNA-encoded peptides in various organelles. A subset of studies have reported on the subcellular localization of ncRNA-encoded peptides, which are mainly localized to the nucleus, cytoplasm, plasma membrane, mitochondria, Golgi apparatus, and endoplasmic reticulum. Some ncRNA-encoded peptides can be sorted to endosomes and exosomes. In addition, a small number of ncrna-encoded peptides can be secreted extracellularly

Fig. 3

Timeline of the discoveries in ncRNA-encoded peptides. Timeline of first reports of different types of ncRNA-encoded peptides and first reports of different types of ncRNA-encoded peptides in cancer

Fig. 4

Methods for prediction and characterization of ncRNA-encoded peptides. A Bioinformatics prediction of sORF. B Ribo-seq screening of ncRNAs with coding potential. C Mass spectrometry identification of peptide sequences. D Detection of TAG for mutated start codon fusions in ncRNA sORFs. E CRISPR/Cas9 knock-in TAG to detect endogenous expression of ncRNA-encoded peptides. F Generation of target antibodies to detect endogenous expression of ncRNA-encoded peptides. G Sucrose density gradient separation to detect ribosomal enrichment on ncRNAs

Fig. 5

Effects of ncRNA-encoded peptides on the biological behavior of cancer cells. NcRNA-encoded peptides can affect cancer cell proliferation, metastasis, the tumor vasculature, stemness, malignant differentiation, senescence, ferroptosis, chemoresistance, target drug resistance and radioresistance

Fig. 6

Different perspectives summarize ncRNA-encoded peptides associated with proliferation and metastasis. A NcRNA-encoded peptides regulate cancer cell proliferation and metastasis through multiple signaling pathways. B NcRNA-encoded peptides regulate cancer cell proliferation and metastasis by affecting specific proteins. C NcRNA-encoded peptides regulate cancer cell proliferation and metastasis through metabolic reprogramming. D NcRNA-encoded peptides in different organelles can influence cancer cell proliferation and metastasis. E NcRNA-encoded peptides regulate cancer cell proliferation and metastasis through other mechanisms

Fig. 7

The role of ncRNA-encoded peptides in vasculature, stemness and malignant differentiation. A NcRNA-encoded peptides regulate lymphangiogenesis and angiogenesis through various molecular mechanisms. B NcRNA-encoded peptides regulate stemness through various molecular mechanisms. C NcRNA-encoded peptides regulate malignant differentiation through various molecular mechanisms

Fig. 8

The role of ncRNA-encoded peptides in senescence and ferroptosis. A NcRNA-encoded peptides regulate senescence through various molecular mechanisms. B NcRNA-encoded peptides regulate ferroptosis through various molecular mechanisms

Fig. 9

The role of ncRNA-encoded peptides in therapeutic resistance and therapeutic sensitivity. A NcRNA-encoded peptides act as oncogenes that promote DOX, cisplatin, pemetrexed, PARP/ATR/CDK4/6 inhibitors, EGFR-TKI, IR, epirubicin and camptothecin resistance in cancer cells. B NcRNA-encoded peptides act as tumor suppressor genes that promote oxaliplatin, sorafenib, TMZ, EGFR-TKI and IR sensitivity in cancer cells

Fig. 10

NcRNA-encoded peptides regulate the biological behavior of cancer cells through PTMs. A NcRNA-encoded peptides can regulate protein phosphorylation by affecting protein kinases or protein phosphatases, binding to protein phosphorylation sites, affecting receptor-ligand binding, and affecting second messengers, which in turn modulates cancer cell proliferation, metastasis, angiogenesis, stemness, and ferroptosis. B NcRNA-encoded peptides can regulate protein ubiquitination by affecting E3 ligases or deubiquitinating enzymes and binding to protein ubiquitination sites, which in turn modulates cancer cell proliferation, metastasis, EGFR-TKI sensitivity, sorafenib sensitivity and ferroptosis. C NcRNA-encoded peptides can regulate cancer cell proliferation and metastasis by affecting phosphorylation-mediated ubiquitination. D NcRNA-encoded peptides can regulate cancer cell targeted drug resistance, radioresistance and chemoresistance by affecting PARylation. E NcRNA-encoded peptides can regulate cancer cell stemness by affecting phosphorylation and cholesterol modification. F NcRNA-encoded peptides can regulate protein SUMOylation by affecting SUMO E3 ligases and binding to SUMO protein, which in turn modulate cancer cell malignant differentiation and ferroptosis

Fig. 11

Potential applications of ncRNA-encoded peptides. The prospective role of ncRNA-encoded peptides in cancer clinical treatment: therapeutic targets, diagnostic and prognostic biomarkers, cancer vaccines, drug synergism, and anticancer therapy