SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

Abstract

Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5′-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation. We demonstrate that the CK1α 5′-UTR functions as an IRES element in HCT-116 colon cancer cells to promote cap-independent translation. Using tobramycin-affinity RNA-pulldown assays coupled with identification via mass spectrometry, we identified several CK1α 5′-UTR-binding proteins, including SFPQ. We show that RNA interference targeting SFPQ reduced CK1α protein abundance and partially blocked RAS-mutant colon cancer cell growth. Importantly, transcript and protein levels of SFPQ and other CK1α 5′-UTR-associated RNA-binding proteins (RBPs) are found to be elevated in early stages of RAS-mutant cancers, including colorectal and lung adenocarcinoma. Taken together, our study uncovers a previously unappreciated role of RBPs in promoting RAS-mutant cancer cell growth and their potential to serve as promising biomarkers as well as tractable therapeutic targets in cancers driven by oncogenic RAS.

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“…4A ) [ 26 ]. Other proteins included SFPQ, which modulates 5′‐UTR mediated translational control [ 27 ], and ribosomal proteins (RPL11, RPSA, RPS5, and MRPL1), which can bind the ribosome assembly factor RNA helicases [ 28 , 29 ]. Several mitochondrial proteins (NDUFA9, MT‐CYB, MT‐ATP6, SDHD, and ATP6V0B) were observed in the DTI networks.…”

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“…A recent study has demonstrated that CK1α expression is regulated by an IRES in the 5‘-UTR of CK1α mRNA. From analysis using HCT-116 cells, SFPQ and PSPC1 were identified as interacting proteins of this IRES, and SFPQ knockdown decreases the CK1α protein abundance, which suggests that SFPQ activates the IRES-dependent translation of CK1α [ 97 ]. SFPQ silencing suppresses in vitro proliferation of HCT-116 cells via KRAS mutation-dependent manner, and exogenous CK1α overexpression rescues this growth defect.…”