t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2

Abstract

Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.

ZHX1 Promotes the Proliferation, Migration and Invasion of Cholangiocarcinoma Cells

“…In Hodgkin’s lymphoma, ZHX2 expression was diminished and ZHX2 knockdown suppressed genes promoting differentiation and apoptosis [27]. Furthermore, it was recently reported ZHX1 inhibited gastric cancer cell proliferation [17], and that ectopic ZHX1 expression decreased proliferation of SMMC-7721 cells (a hepatocellular carcinoma cell line) [11].…”

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

“…Although this study did not set out to identify the impact of this polymorphism in a diseased population, it may serve as a pilot study to suggest that the impact of this polymorphism in various disease states such as PH or systemic hypertension is reasonable. The scope of interest may even extend beyond that of cardiorespiratory disease because recent investigations into PDE5A have described it as an oncogene and possible therapeutic target in Hodgkin lymphoma and hepatic neoplasia 24, 25. The canine PDE5A gene possesses a least 1 amino acid‐altering polymorphism (PDE5A:E90K) that appears to confer the functional consequence of decreased cGMP concentrations in healthy dogs and warrants further investigation.…”

Roles of zinc-fingers and homeoboxes 1 during the proliferation, migration, and invasion of glioblastoma cells

“…21 In Hodgkin's lymphoma, ZHX2 knockdown reduced the expressions of differentiation-and apoptosis-promoting genes, suggesting ZHX2 acted as tumor suppressor. 22 suppressed proliferation and its knockdown in gastric cancer cells (SGC-7901-SH) increased proliferation. 15,16 However, other studies have reported that ZHX1 may be an oncogene.…”