Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer

Abstract

PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer.

Greatwall kinase at a glance

“…It remains to be understood how Gwl promotes GSK3 dephosphorylation and activation. In line with a role of Gwl in oncogenesis, its overexpression has been identified in a myriad of human tumours in the last three years, including breast (Alvarez-Fernandez et al, 2017;Zhuge et al, 2017), colon (Vera et al, 2015) and head and neck squamous carcinomas (Wang et al, 2014). Moreover, Gwl levels have evolved as a biomarker in these cancers with prognostic value for survival, recurrence and metastasis (Alvarez-Fernandez et al, 2017;Wang et al, 2014;Zhuge et al, 2017).…”

“…In line with a role of Gwl in oncogenesis, its overexpression has been identified in a myriad of human tumours in the last three years, including breast (Alvarez-Fernandez et al, 2017;Zhuge et al, 2017), colon (Vera et al, 2015) and head and neck squamous carcinomas (Wang et al, 2014). Moreover, Gwl levels have evolved as a biomarker in these cancers with prognostic value for survival, recurrence and metastasis (Alvarez-Fernandez et al, 2017;Wang et al, 2014;Zhuge et al, 2017). Additionally, Gwl has been highlighted as a potential new therapeutic target for several cancers, such as acute myeloid leukemia (Tzelepis et al, 2016), head and neck squamous cell carcinoma (Wang et al, 2014) and thyroid carcinoma (Anania et al, 2015).…”

“…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).…”

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…Accordingly, timely reperfusion therapy is important as an effective approach to reverse the damage to brain function and thus improve the prognosis in patients with ischaemia stroke . However, reperfusion itself brings about additional damage to ischaemic brain tissue, and this is termed as ‘ischaemia reperfusion injury’ which accounts for increased perioperative mortality . Although many experiments have been conducted over several decades in this field the molecular features, the underlying cerebral ischaemia reperfusion injury (IRI) have not been described comprehensively …”

AKT regulates mitotic progression of mammalian cells by phosphorylating MASTL

“…In addition to its role at mitotic entry, MASTL plays an important role in mitotic exit as well, where upon its deactivation has been seen to be an essential requirement for the cells to exit from mitosis [9,10]. Being so critical for mitosis, MASTL has been investigated in various types of carcinomas and has been seen to be up regulated in a number of malignancies [11][12][13]. Role of MASTL in tumor progression has been attributed to the increased rate of cell proliferation driven by activation/up-regulation of this kinase in tumor cells.…”