Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. Genetic ablation of TMEM9 inhibits colorectal cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/β-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal cancer treatment.
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Microarray data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GDS2947. The TMEM9 expression data in CRC cells were derived from the cBioportal using the TCGA Research Network (http://cancergenome.nih.gov/) and Genetech data sets. The data set derived from this resource that supports the findings of this study is available in Oncomine (https://www.oncomine.org/resource). TMEM9 expression data were also derived from cBioportal (http://www.cbioportal.org/) and the COSMIC database (Catalogue of Somatic Mutations in Cancer) (https://cancer.sanger.ac.uk/cosmic). Source data for Figs. 1–8 and Supplementary Figs. 1–4 are provided as Supplementary Table 4. All other data supporting the findings of this study are available from the corresponding author on reasonable request.
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The authors thank X. Wang and A. Sharma for technical assistance. This work was supported by the University of Texas McGovern Medical School (startup funding to R.K.M.), the Cancer Prevention Research Institute of Texas (RP140563 to J-.I.P.), the National Institutes of Health (R01 CA193297-01 to J-.I.P.; 5R01 GM107079 to P.D.M.; K01DK092320 to R.K.M.; R01 GM126048 to W.W.), the Department of Defense Peer Reviewed Cancer Research Program (CA140572 to J-.I.P.), a Duncan Family Institute for Cancer Prevention and Risk Assessment Grant (IRG-08-061-01 to J-.I.P.), a Center for Stem Cell and Developmental Biology Transformative Grant (MD Anderson Cancer Center to J-.I.P.), an Institutional Research Grant (MD Anderson Cancer Center to J-.I.P.), a New Faculty Award (MD Anderson Cancer Center Support Grant to J-.I.P.), a Metastasis Research Center Grant (MD Anderson to J-.I.P.) and a Uterine SPORE Career Enhancement Program (MD Anderson to J-.I.P.). The core facility (DNA sequencing and Genetically Engineered Moue Facility) was supported by an MD Anderson Cancer Center Support Grant (CA016672).