Abstract
Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.
Highlights
In Saccharomyces cerevisiae and was strongly associated with cell cycle arrest; it has been called Cdc48 [1]
A few years later, Fang et al documented that long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1), which binds miR-1295p, is overexpressed in hepatocellular carcinoma (HCC) tissues and cell lines compared to normal cells and tissues, suggesting that it potentially represents a new target in HCC diagnosis and treatment [69]
As described in the second section, increased Valosin-containing protein (VCP) expression has been detected in various cancers and correlated with progression, prognosis, and metastatic potential
Summary
VCP/p97 has been implicated in several pathways related to protein quality control, including ERAD, mitochondria-associated degradation, ribosome-associated degradation and proteasomal degradation. Misfolded proteins undergo ubiquitination and are extracted from the membranes by VCP/p97 [32]. These dislodged ERAD substrates are targeted for degradation by the proteasome [33]. VCP/p97 facilitates mitochondria-associated degradation, a process that eliminates aberrant polypeptides from the mitochondrial outer membrane to maintain mitochondrial protein homeostasis [34]. VCP/p97 is involved in ribosome-associated degradation, a process that degrades aberrant nascent polypeptides stalled on ribosomes [37]. VCP/p97 is recruited by a ribosome-associated factor named RQC1 together with the ubiquitinated substrate and extracts defective polypeptides from the ribosome to promote their degradation by the proteasome [38]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
