C18orf1 Regulates Cancer Cell Proliferation And Migration

C18orfl,also known as low density lipoprotein receptor class A domain containing 4(LDLRAD4),is a protein associated with nervous diseases.The protein structure of C18orf1 and TMEPAI is very similar,containing two PY domains and SIM motif.C18orf1 has low expression in normal cells,and is highly expressed in many cancer cells,but the mechanism is unclear.So it can be speculated that C18orf1 regulates tumor cells proliferation and migration as TMEPAI through interaction with E3 ubiquitin ligase Nedd4 and the regulating the TGF-β signaling.In this study,knockdown C18orf1 in HepG2 cells or HeLa cells transiently overexpress C18orf1 found that knockdown C18orf1 inhibiting cancer cell proliferation,migration,invasion and the cell cycle arrest in S phase,and overexpression of C18orf1 promote cancer cell proliferation and migration.Using yeast two hybrid technology found C18orf1 interact with Nedd4,Smurfl,WWP1 and Nedd41.GST pull-down experiments further confirmed C18orf1 interacts with Nedd4 E3 ubiquitin ligase via its PY motif.Subsequent studies found that overexpression of C18orf1-WT promote cell growth,inhibition of TGF-β signal,but overexpression of C18orf1-2YA mutant cannot.In addition,C18orf1 is localized to the lysosome and late endosome.Blocking C18orf1-Nedd4 interaction inhibits the ubiquitination of C18orf1,and results in transport of C18orf1 to the cell membrane.Studies have shown that C18orfl like TMEPAI,through interact with Nedd4 occurred ubiquitin by PY domain that promote cancer cell proliferation and migration,regulate the TGF-β signal and its cellular localization.Therefore,C18orf1 for targets for the treatment of cancer offers a new strategy.