A novel amplification gene PCI domain containing 2 (PCID2) promotes colorectal cancer through directly degrading a tumor suppressor promyelocytic leukemia (PML)

Abstract

AbstractUsing whole genome sequencing, PCI Domain Containing 2 (PCID2) was identified to be amplified in colorectal cancer (CRC). In this study, we investigated the expression, biological function, molecular mechanism, and clinical implication of PCID2 in CRC. PCID2 mRNA and protein expression were higher in CRC cells and tumor tissues compared to healthy colonic tissues. The copy number of PCID2 was positively correlated with its mRNA expression. Multivariate analysis revealed that PCID2 is an independent prognostic factor for CRC recurrence. Functional studies showed that PCID2 promoted cell growth, cell cycle progression, and cell migration/invasion, while apoptosis was suppressed. Moreover, PCID2 promoted xenograft growth and lung metastasis in nude mice. Using co-immunoprecipitation and mass spectroscopy, we showed that PCID2 binds to promyelocytic leukemia (PML), a tumor suppressor involved in non-canonical β-catenin signaling. PCID2 promoted the degradation of PML via poly-ubiquitination, which in turn, induced Wnt/β-catenin signaling while simultaneously repressing ARF-p53 pathway. Thus, these results demonstrated that PCID2 functions as an oncogene in CRC by enhancing canonical Wnt/β-catenin signaling and inhibition of CTNNB1-ARF-p53 axis. PCID2 promoted canonical Wnt/β-catenin signaling in CRC via degradation of PML. PCID2 may serve as an independent prediction marker for CRC recurrence.