RBMY, a novel inhibitor of glycogen synthase kinase 3β, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma

Abstract

Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6-9 years, indicative of a possible role of the Y chromosome-encoded oncogene in addition to an androgenic effect. The discovery of oncogenic activation of RBMY (RNA-binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/ Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt-3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self-renewal, chemoresistance, cell-cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation-inactivation of glycogen synthase kinase 3b by RBMY, thereby impeding the glycogen synthase kinase 3b-dependent degradation of b-catenin and eventually inducing the nuclear entry of b-catenin for the transcription of downstream oncogenes. Conclusion: RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3b activity, leading to aberrant activation of Wnt/b-catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients. (HEPATOLOGY 2015;62:1480-1496 H epatocellular carcinoma (HCC) is prevalent worldwide and currently the second leading cause of cancer-related mortality.1 It develops primarily in cirrhotic livers, which are frequently the result of chronic hepatitis B or C viral infection; and a global male predominance has been reported for HCC patients of all ages.1,2 Our previous study indicated that the male to female ratio of HCC patients is higher in

The regulation of β-catenin activity and function in cancer: therapeutic opportunities

“…RNA-binding motif on Y chromosome (RBMY) is overexpressed in male HCC tissues. RBMY induces Ser9 phosphorylation-induced inactivation of GSK3β, thereby impeding the GSK3β-mediated degradation of β-catenin and subsequently increasing stemness of HCC [37]. Besides RBMY, HBx-activated AKT and ERKs also phosphorylate and inactivate GSK3β, leading to stabilization of β-catenin and CyclinD1 gene transcription, and promoting the development of HCC [38].…”

The Wnt signaling pathway in cancer

“…type II diabetes 36 , degenerative (e.g. Parkinson’s 37 , Alzheimer’s 38 ) and particularly cancers (hepatocarcinoma 39,40 , colon cancer 41 , leukemias 42 .…”

Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma (Review)

“…The sex disparity of HCC has demonstrated that the ratio of estrogen and testosterone levels may be associated with the initiation and progression of HCC, suggesting that active estrogen-and androgen-mediated signaling pathways may regulate the risk of HCC (7,8). In recent years, increasing attention has been focused on the genetic alterations of sex chromosomes, which may be responsible for the sex disparity in HCC (9)(10)(11). Considerable efforts have been exerted in exploring the molecular mechanisms involved in the sex disparity in HCC (7-9).…”