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F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear ?-catenin function.

ABSTRACT: Aberrant activation of ?-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/?-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear ?-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of ?-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of ?-catenin. Therefore, depletion of FBXO16 leads to increased levels of ?-catenin, which then promotes cell invasion, tumor growth, and EMT of cancer cells. Furthermore, FBXO16 and ?-catenin share an inverse correlation of cellular expression in clinical breast cancer patient samples. In summary, we propose that FBXO16 functions as a putative tumor suppressor by forming an SCFFBXO16 complex that targets nuclear ?-catenin in a unique manner for ubiquitination and subsequent proteasomal degradation to prevent malignancy. This work suggests a novel therapeutic strategy against human cancers related to aberrant ?-catenin activation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

SUBMITTER: Paul D

PROVIDER: S-EPMC6619347 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear β-catenin function.

Paul Debasish D Islam Sehbanul S Manne Rajesh Kumar RK Dinesh U S US Malonia Sunil K SK Maity Biswanath B Boppana Ramanamurthy R Rapole Srikanth S Shetty Praveen Kumar PK Santra Manas Kumar MK

The Journal of pathology 20190308 3

Aberrant activation of β-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/β-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear β-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interac ...[more]

PMID: 30714168

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Project description:BACKGROUND & AIMS:Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC). METHODS:We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. Spdef(-/-)and wild-type mice (controls) were either bred with Apc(Min/+) mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of Spdef also was induced transiently by administration of tetracycline to Spdef(dox-intestine) mice with established tumors, induced by the combination of AOM and DSS or by breeding with Apc(Min/+) mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells. RESULTS:In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. Spdef(-/-); Apc(Min/+) mice developed approximately 3-fold more colon tumors than Spdef(+/+); Apc(Min/+) mice. Likewise, Spdef(-/-) mice developed approximately 3-fold more colon tumors than Spdef(+/+) mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in Spdef(-/-) mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from Spdef(dox-intestine); Apc(Min/+) mice and in Spdef(dox-intestine) mice after administration of AOM + DSS. SPDEF inhibited the expression of ?-catenin-target genes in mouse colon tumors, and interacted with ?-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC. CONCLUSIONS:SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.

Dataset Information

F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear ?-catenin function.

Publications

F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear β-catenin function.

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