Single-cell RNA binding protein regulatory network analyses reveal oncogenic HNRNPK-MYC signalling pathway in cancer

A computational pipeline and webserver identify regulators of RNA-binding proteins (RBPs) at single-cell resolution and are applied to determine the role of RBP HNRNPK in cancer. RNA-binding proteins (RBPs) are key players of gene expression and perturbations of RBP-RNA regulatory network have been observed in various cancer types. Here, we propose a computational method, RBPreg, to identify the RBP regulators by integration of single cell RNA-Seq (N = 233,591) and RBP binding data. Pan-cancer analyses suggest that RBP regulators exhibit cancer and cell specificity and perturbations of RBP regulatory network are involved in cancer hallmark-related functions. We prioritize an oncogenic RBP-HNRNPK, which is highly expressed in tumors and associated with poor prognosis of patients. Functional assays performed in cancer cells reveal that HNRNPK promotes cancer cell proliferation, migration, and invasion in vitro and in vivo. Mechanistic investigations further demonstrate that HNRNPK promotes tumorigenesis and progression by directly binding to MYC and perturbed the MYC targets pathway in lung cancer. Our results provide a valuable resource for characterizing RBP regulatory networks in cancer, yielding potential biomarkers for precision medicine.

Automated summary

This study proposes a computational method, RBPreg, to identify the regulators of RNA-binding proteins (RBPs) at single-cell resolution by integrating single cell RNA-Seq and RBP binding data. The results suggest that RBP regulators exhibit cancer and cell specificity, and perturbations of RBP regulatory network are involved in cancer hallmark-related functions. The study focuses on an oncogenic RBP, HNRNPK, which is highly expressed in tumors and associated with poor prognosis.