TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling

Nat Cell Biol. 2018 Dec;20(12):1421-1433. doi: 10.1038/s41556-018-0219-8.

Youn-Sang Jung ¹, Sohee Jun ¹, Moon Jong Kim ¹, Sung Ho Lee ¹, Han Na Suh ¹, Esther M Lien ¹, Hae-Yun Jung ¹, Sunhye Lee ¹, Jie Zhang ¹, Jung-In Yang ¹, Hong Ji ², Ji Yuan Wu ³, Wenqi Wang ⁴, Rachel K Miller ² ⁵ ⁶ ⁷, Junjie Chen ¹ ⁶ ⁷, Pierre D McCrea ² ⁶ ⁷, Scott Kopetz ³, Jae-Il Park ⁸ ⁹ ¹⁰

Affiliations

1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
5 Department of Pediatrics, The University of Texas McGovern Medical School, Houston, TX, USA.
6 Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, TX, USA.
7 Program in Genes and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jaeil@mdanderson.org.
9 Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center and MD Anderson Cancer Center, Houston, TX, USA. jaeil@mdanderson.org.
10 Program in Genes and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jaeil@mdanderson.org.

PMID: 30374053 DOI: 10.1038/s41556-018-0219-8

Abstract

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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