Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival.

A large body of evidence suggests that B-cell lymphomas with enhanced Myc expression are associated with an aggressive phenotype and poor prognosis, which makes Myc a compelling therapeutic target. Phosphodiesterase 4B (PDE4B), a main hydrolyzer of cyclic AMP (cAMP) in B cells, was shown to be involved in cell survival and drug resistance in diffuse large B cell lymphomas (DLBCL). However, the interrelationship between Myc and PDE4B remains unclear. Here, we first demonstrate the presence of the Myc-PDE4B feed-forward loop, in which Myc and PDE4B mutually reinforce the expression of each other. Next, the combined targeting of Myc and PDE4 synergistically prevented the proliferation and survival of B lymphoma cells in vitro and in a mouse xenograft model. We finally recapitulated this combinatorial effect in Eµ-myc transgenic mice; co-inhibition of Myc and PDE4 suppressed lymphomagenesis and restored B cell development to the wild type level that was associated with marked reduction in Myc levels, unveiling the critical role of the Myc-PDE4B amplification loop in the regulation of Myc expression and the pathogenesis of B cell lymphoma. These findings suggest that the disruption of the Myc-PDE4B circuitry can be exploited in the treatment of B cell malignancies.

Phosphodiesterase 4B is an effective therapeutic target in colorectal cancer.

Identification of new therapeutic targets may improve the survival rate of patients with colorectal cancer (CRC). Recent studies have suggested that the level of phosphodiesterase 4B (PDE4B) is elevated in fatal/refractory diffuse large B-cell lymphoma (DLBCL), and therapeutic efficacy of a PDE4 inhibitor in B-cell lymphoma has been successfully tested in clinical settings. Here, we show that PDE4B is a potential therapeutic target in CRC. Treatment with forskolin, an activator of adenylyl cyclase (AC), increased intracellular cyclic AMP (cAMP) levels in PDE4B-low, but not PDE4B-high cells, indicating that PDE4B was a major regulator of cAMP levels in CRC cells. Furthermore, cAMP modulated the activities of AKT and AMPK in a PDE4B-dependent manner, which was associated with a marked decrease in mTOR-Myc signals and oncogenic properties of CRC cells such as anchorage-independent growth and colony formation. We found that the Myc proto-oncogene was a crucial downstream target of the AKT/mTOR and AMPK/mTOR signals that mediated cAMP-induced anti-tumor effect. A natural polyphenol resveratrol that was reported to have PDE4 inhibitory effects also showed tumor suppressive effects by inhibiting the mTOR-Myc axis. Intriguingly, we identified Myc as a transcriptional activator of PDE4B in CRC cells, which maintains the intracellular cAMP levels low and promotes cell survival. These data suggest that cAMP/PDE4B signals play a significant role in regulating the malignant phenotype of CRC cells and targeting of PDE4B should be actively pursued.

MicroRNA-552 links Wnt signaling to p53 tumor suppressor in colorectal cancer.

The aberrant expression of microRNAs (miRNAs or miRs) has been shown to be associated with the development of various types of cancer, including colorectal cancer (CRC). The increased activation of the Wnt signaling pathway via the loss of the Wnt repressor, adenomatous polyposis coli (APC), is the hallmark of human CRC. In this study, we demonstrate that the activation of the Wnt/c-Myc axis inhibits the expression of the tumor suppressor, p53, via promoting the targeting of p53 by miR­552. Our results revealed that the ectopic expression of miR­552 enhanced cell proliferation, colony formation and resistance to drug-induced apoptosis, suggesting that this miRNA may function as an oncogene. We found that miR­552 displayed oncogenic properties by directly targeting the p53 tumor suppressor. Of note, our genetic and pharmacological experiments revealed that the Wnt/ß-catenin signaling pathway and its major downstream target, c-Myc (hereafter termed Myc), increased the miR­552 levels, and chromatin immunoprecipitation (ChIP) assays revealed they carried out this function by directly binding to their binding sites in the miR­552 promoter region. Given that the functional loss of APC, leading to abnormal Wnt signals, and the absence of p53 protein are common in CRC, these results suggest that miR­552 may serve as an important link between these two events, and this warrants further investigation. Collectively, the data of this study suggest that the inhibition of miR­552 may disconnect elevated Wnt signals from p53 suppression, providing a novel therapeutic strategy for patients with CRC with deregulated Wnt signaling.