Antitumorigenic Effects of ZAKβ, an Alternative Splicing Isoform of ZAK

Abstract

Sterile alpha motif (SAM)- and leucine-zipper-containing kinase (ZAK) plays a role in the regulation of cell cycle progression and oncogenic transformation. The ZAK gene generates two transcript variants, ZAKα and ZAKβ, through alternative splicing. In this study, we identified that ZAKα proteins were upregulated in tumor tissues, whereas ZAKβ proteins were mostly expressed in corresponding normal tissues. The ectopically expressed ZAKβ proteins in cancer cells inhibited cancer cell proliferation as well as anchorage-independent growth. The ZAKβ:ZAKα protein ratio played a role in the regulation of the cyclic adenosine monophosphate (cAMP) signaling pathway, whereas high ZAKβ protein levels led to the activation of cAMP response element binding protein 1 (CREB1) and exerted antitumor properties. Overexpression of ZAKβ or CREB1 cDNAs in cancer cells inhibited anchorage-independent growth and also reduced the levels of cyclooxygenase 2 (Cox2) and β-catenin proteins. Cancer cells treated with doxorubicin (Doxo) resulted in the switching from the expression of ZAKα to ZAKβ and also inhibited cancer cell growth in soft agar, demonstrating that pharmacological drugs could be used to manipulate endogenous reprogramming splicing events and resulting in the activation of endogenous antitumorigenic properties. We showed that the two ZAK transcript variants, ZAKα and ZAKβ, had opposite biological functions in the regulation of tumor cell proliferation in that ZAKβ had powerful antitumor properties and that ZAKα could promote tumor growth.

Prognostic Value and Potential Role of Alternative mRNA Splicing Events in Cervical Cancer

“…For example, GEMIN4-38259-AP and WTAP-78310-AP are favorable prognostic factors, whereas GEMIN4-38260-AP and WTAP-78311-AP are poor prognostic factors for patients with CC (Supplementary Figure S1). The same phenomenon has been observed in previous studies showing that AS of the ZAK gene generated two subtypes (ZAKα and ZAKβ), which perform antagonistic functions (Lee et al, 2018). Similarly, AS generates two isoforms of BCL2L1 gene (BCL-XL and BCL-XS); BCL-XS promotes apoptosis, whereas BCL-XL inhibits apoptosis (Chen and Weiss, 2015).…”

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Gastrointestinal Pan-Adenocarcinomas

“…Further, ZAKα and ZAKβ are two isoforms of ZAK, and they toward contrary way in the proliferation of cancers. ZAKα exerts an anti-neoplastic effect, while ZAKβ has essential antiproliferation properties [ 38 ]. However, the onset and progression of gastrointestinal pan-adenocarcinomas is supposed to suffer substantial aberrant AS events [ 12 ].…”

Inhibition of mitochondrial complex III or dihydroorotate dehydrogenase (DHODH) triggers formation of poly(A) + RNA foci adjacent to nuclear speckles following activation of ATM (ataxia telangiectasia mutated)

“…Etoposide, another topoisomerase II inhibitor, did not cause nuclear poly(A) + RNA accumulation in this study, indicating that DNA DSBs evoked by topoisomerase II inhibitors did not directly induce nuclear poly(A) + RNA accumulation. Additionally, recent reports have shown that anthracyclines affect splicing, but a reliable pathway for their mechanism of action remains unclear [ 67 , 68 ].…”