Dataset Information

TAZ/Wnt-?-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

ABSTRACT: Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated ?-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing ?-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with ?-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-?-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.

SUBMITTER: Lee EJ

PROVIDER: S-EPMC7682393 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

Lee Eun Ji EJ Seo Eunjeong E Kim Jin Won JW Nam Sun Ah SA Lee Jong Young JY Jun Jaehee J Oh Sumin S Park Minah M Jho Eek-Hoon EH Yoo Kyung Hyun KH Park Jong Hoon JH Kim Yong Kyun YK

Proceedings of the National Academy of Sciences of the United States of America 20201029 46

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of <i>PKD1</i> or <i>PKD2</i>, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelia ...[more]

PMID: 33122431

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Project description:Statins are first-line drugs used to control patient lipid levels, but there is recent evidence that statin treatment can lower colorectal cancer (CRC) incidence by 50% and prolong CRC patient survival through mechanisms that are poorly understood. In this study, we found that the treatment of APCmin mice by the mevalonate pathway inhibitor lovastatin significantly reduced the number of colonic masses and improved hypersplenism and peripheral anemia. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) analysis of colonic mass tissues showed a potent inhibitory effect in both Wnt/β-catenin signaling and YAP/TAZ signaling in the lovastatin treatment group. The results of our transcriptomic analyses in RKO indicated that lovastatin regulated several proliferation-related signaling pathways. Moreover, lovastatin suppressed important genes and proteins related to the canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ signaling pathways in RKO and SW480 cells, and these effects were rescued by mevalonic acid (MVA), as confirmed through a series of Western blotting, RT-PCR, and reporter assays. Given that statins suppress oncogenic processes primarily through the inhibition of Rho GTPase in the mevalonate pathway, we speculate that lovastatin can inhibit certain Rho GTPases to suppress both canonical Wnt/β-catenin signaling and alternative Wnt-YAP/TAZ signaling. In RKO cells, lovastatin showed similar inhibitory properties as the RhoA inhibitor CCG1423, being able to inhibit β-catenin, TAZ, and p-LATS1 protein activity. Our results revealed that lovastatin inhibited RhoA activity, thereby suppressing the downstream canonical Wnt/β-catenin and alternative Wnt-YAP/TAZ pathways in colon cancer cells. These inhibitory properties suggest the promise of statins as a treatment for CRC. Altogether, the present findings support the potential clinical use of statins in non-cardiovascular contexts and highlight novel targets for anticancer treatments.

Dataset Information

TAZ/Wnt-?-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

Publications

TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease.

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