KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

Abstract

Studies have suggested that Epithelial–Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas.

Epigenetic Regulation of Tumor Suppressors byHelicobacter pyloriEnhances EBV-Induced Proliferation of Gastric Epithelial Cells

“…(H) Using the standard trypan blue exclusion assay method, proliferation of GC cells under different conditions was scored. (I) A colony formation assay was performed using a previously described method ( 68 ) and crystal violet staining. (J) A model depicting the modulation of the cell cycle, apoptosis, and DNA damage repair pathways that can lead to tumorigenesis of EBV- H. pylori -positive gastric epithelial cells.…”

“…A cell proliferation assay was performed using trypan blue exclusion and crystal violet staining methods as previously described ( 67 , 68 ). Brief descriptions are provided in Text S1 and elsewhere in Materials and Methods.…”

SATB2-AS1 Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent Snail Transcription and Epithelial–Mesenchymal Transition

“…However, Snail-overexpressing cells can respond to mitogenic signals by transiently decreasing p21 expression, which favors the transition to S phase (43). The study also reported that Snail repressed p21 expression in infected B cells contributing to KSHV induced B-cell oncogenesis (44). Snail knockdown was reported to led to the upregulation of p21 and downregulation of Cdc2, causing a decrease of G 1 and S periods and an increase of the G 2 -M population (45).…”

Cellular responses to human cytomegalovirus infection: Induction of a mesenchymal-to-epithelial transition (MET) phenotype

“…In Epstein-Barr virus (EBV)-transformed B cells, expression of miR-200 RNAs, which directly induces MET in cancer models (30), causes a switch from latency to lytic replication (31). Similarly, during Kaposi's sarcoma-associated herpesvirus (KSHV) infection of B cells, the latency-associated nuclear antigen (LANA) induces mesenchymal features by up-regulating SNAIL (32). Suppression of LANA breaks latency (33), inhibits SNAIL, and induces epithelial genes including CDH1 (32), features consistent with MET.…”