Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

Abstract

Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) downregulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatment of cancer cells with a unique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

“…6A-C). The involved locus spanned ;2 Mb in length and disrupted genomic structures of several genes including ACTBL2 and a candidate oncogene, PDE4D (Lin et al 2013). …”

Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D

“…This study showed a connection between PDE4D and AMPK in cancer/cellcycle dynamics (46). Further depletion of PDE4D can cause apoptosis (10%-40%) in multiple types of cancer cells which have elevated expression level of PDE4D (26).…”

“…2D). The overexpression of PDE4D has been observed in multiple types of cancer cells originating from the central nervous system (CNS), lung, breast, and melanomas (26). But, so far, there has been no report that the elevated expression of PDE4D is mutation-specific in cancer.…”

“…These results indicate that the regulation of PDE4D expression is at the downstream of STK11 and AMPK signaling. Previously, PDE4D has been known as a tumor-promoting factor (26). We investigated whether inhibition of PDE4D would selectively inhibit the growth of cancer cells with aberrant STK11.…”

“…Indeed, PDE4 has previously been implicated in cancer pathophysiology by altering proliferation and angiogenesis in lung cancer (44). The association of PDE4D expression and cancer progression has been reported in multiple types of cancer (26). Recently, PDE4D7, one of PDE4D isoforms, has been reported as an androgen-independent marker with a role in regulation of prostate cancer cell proliferation (45).…”