MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/β-catenin signaling

Abstract

BackgroundChemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.MethodsWe utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.ResultsHere, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.ConclusionOverall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0848-3) contains supplementary material, which is available to authorized users.

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

“…Similar results were also observed in Chinese medicine including luteolin and Sanguisorba officinalis which could induce apoptosis by enhancing the Bax and caspase-3 expression and suppressing Bcl-2 expression through Wnt/β-catenin signaling in CRC cell lines [31,32]. MASTL induces resistance to 5-fluorouracil (5-FU) through regulating antiapoptotic proteins survivin and Bcl-xL via the Wnt/β-catenin signaling pathway [33]. Thus, the crucial roles of Wnt/βcatenin signaling in apoptosis give it a status in the chemoresistance of CRC, and the underlying mechanisms need further exploration.…”

PLAGL2 promotes epithelial–mesenchymal transition and mediates colorectal cancer metastasis via β-catenin-dependent regulation of ZEB1

“…Microtubuleassociated serine/threonine kinase like (MASTL) induced CRC progression and chemoresistance by activating the β-catenin signalling pathway. 45 The ring finger protein 6(RNF6)-mediated degradation of transducin-like enhancer of split 3 (TLE3) remarkably impeded the binding of TLE3 with TCF4/LEF, which promoted the recruitment of β-catenin to TCF4/LEF and activated β-catenin signalling in CRC. 46 Our study demonstrated that PLAGL2 was significantly associated with the expression of βcatenin.…”

Greatwall kinase at a glance

“…Recent evidence from a variety of model systems has shown that, besides its primordial role in mitotic division, Gwl also contributes in a significant extent to tumorigenic processes (Alvarez-Fernandez et al, 2017;Uppada et al, 2018;Vera et al, 2015;Dahlhaus et al, 2016;Nagel et al, 2015). Upregulation of Gwl activity promotes cell transformation and increases cell proliferation in several immortalized cells lines and in primary human fibroblasts (Vera et al, 2015).…”