Inactivation of the putative ubiquitin-E3 ligase PDLIM2 in classical Hodgkin and anaplastic large cell lymphoma

Abstract

Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed–Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbol 12-myristate 13-acetate (PMA) stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis.

Systematic profiling identifies PDLIM2 as a novel prognostic predictor for oesophageal squamous cell carcinoma (ESCC)

“…Some previous studies reported that PDLIM2 expression was also regulated by the promoter methylation that blocks its transcription in colon cancer, 26 ovarian cancer 28 and classical Hodgkin and anaplastic large cell lymphoma. 29 However, whether its expression is related to the methylation status of its promoter in ESCC is still not clear.…”

Tsc2 mutation rather than Tsc1 mutation dominantly causes a social deficit in a mouse model of tuberous sclerosis complex

“…Pdlim2 encodes an E3 ubiquitin ligase and ubiquitinates STAT3 and STAT4 to lead to their degradation [55,56]. Pdlim2 is reported to be associated with tumor suppression [57][58][59] and tumorigenesis [60, 61], but its function in the nervous system remains unknown.…”

PDZ and LIM domain protein 2 plays dual and context-dependent roles in breast cancer development

“…The PDLIM2 gene is repressed in different cancers, which implies its tumor suppressive role. Repression and a tumor suppressive role of PDLIM2 were observed in ATL induced by HTLV1 virus [26–29], Kaposi sarcoma [30], ovarian cancer [31], gastric cancer [32], colon cancer [12], Hodgkin lymphoma [33] and breast cancer [34, 35]. In contrast to the above studies, a pro-oncogenic role and enhanced expression of PDLIM2 were observed in castration-resistant prostate cancer cells [5, 9, 36], invasive breast cancer cell lines and breast carcinomas [9, 11].…”