A loss of FUS/TLS function leads to impaired cellular proliferation

Abstract

Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional RNA/DNA-binding protein that is pathologically associated with cancer and neurodegeneration. To gain insight into the vital functions of FUS and how a loss of FUS function impacts cellular homeostasis, FUS expression was reduced in different cellular models through RNA interference. Our results show that a loss of FUS expression severely impairs cellular proliferation and leads to an increase in phosphorylated histone H3, a marker of mitotic arrest. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with multiple processes, some of which influence cell proliferation including cell cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. FUS knockdown also correlated with increased expression of the closely related protein EWS (Ewing's sarcoma). We demonstrate that the maladaptive phenotype resulting from FUS knockdown is reversible and can be rescued by re-expression of FUS or partially rescued by the small-molecule rolipram. These results provide insight into the pathways and processes that are regulated by FUS, as well as the cellular consequences for a loss of FUS function.

LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas

“…FUS belongs to the FET family and it encodes a multifunctional RNA-binding protein which is highly associated with tumor progression. The overexpression of FUS can promote growth inhibition and apoptosis of prostate cancer [35, 36]. …”

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

“…54,55 A loss of FUS/ TLS results in decreased cellular proliferation, impaired RNA processing, and increased expression of the closely related Ewing's sarcoma protein EWS. 56 Indeed, the transactivation domains of the TET family of RNA-binding proteins (such as FUS and EWS) may be interchangeable and FUS/ERG fusions have been reported in Ewing's sarcoma patients. 57 We also observed two long antisense RNAs of unknown biologic significance, MAPT-AS1 in Ewing's sarcoma and DLX6-AS1 in synovial sarcoma.…”

Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma

“…Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional DNA/RNA‐binding protein associated with cancer and neurodegeneration. Some articles revealed that FUS acted as a tumor suppressor and its knockdown increased cell proliferation . Recently, FUS has been shown to interact with a number of lncRNAs in neuron diseases .…”

“…Some articles revealed that FUS acted as a tumor suppressor and its knockdown increased cell proliferation. (24,25) Recently, FUS has been shown to interact with a number of lncRNAs in neuron diseases. (26) Wang et al (27) reported that FUS could be directed to the regulatory regions of target genes by lncRNA transcripts induced by DNA damage signals.…”