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

Abstract

SUMMARY 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 (CRC). Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of v-ATPase, a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/β-catenin signaling via lysosomal degradation of APC. Moreover, TMEM9 transactivated by β-catenin functions as a positive feedback regulator of Wnt signaling in CRC. Genetic ablation of TMEM9 inhibits CRC 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 signaling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for CRC treatment.

The EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

“…TMEM9, for example, has been established as a promoter of intestinal tumorigenesis by direct regulation of the v-ATPase, which favors the activation of the Wnt/-catenin pathway. The authors have described that TMEM9 binds to and facilitates assembly of the v-ATPase, being key for the maintenance of the pH in the acidic vesicles [27]. Similar to these results, the downregulation of TMEM167A strongly increased the pH of acidic vesicles.…”

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

“…42 Alternatively, increased vesicle acidification in colorectal cancer has been shown to promote APC degradation via the endolysosomal pathway, leading to enhanced β-catenin signaling. 43 Nevertheless, the roles of endosome trafficking and Wnt/β-catenin signaling in oral dysplasia remain unexplored, and hence, our findings showing that increased Rab5 activity, endosomal sequestration of the destruction complex, and nuclear localization of β-catenin, contribute to understanding the relevance of this mechanism in early oral lesions.…”

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

“…Importantly, recent studies revealed that APC mutation is insufficient to fully activate Wnt signaling. Furthermore, even if APC is mutated, mutant APC still negatively regulates β-catenin to some extent 39,40 , which will be discussed later.…”

“…The β-catenin paradox Wnt signaling hyperactivation by mutations in β-catenin destruction complex components or β-catenin itself contributes to tumorigenesis. In addition to APC mutations, β-catenin can be further activated by additional layers of regulation 39,40,[111][112][113][114][115][116][117] , which demonstrated the complexity of Wnt signaling deregulation in cancer. Accumulating evidence supports the notion that additional regulatory processes contribute to Wnt signaling hyperactivation in cancer, as demonstrated in the following examples.…”

“…Accumulating evidence supports the notion that additional regulatory processes contribute to Wnt signaling hyperactivation in cancer, as demonstrated in the following examples. (a) Mutant APC is still able to downregulate β-catenin 39,40 . (b) Even in the presence of APC mutations, blockade of WNT ligands triggers apoptosis or growth inhibition 40,113,118 .…”