Cancer is a complex and heterogeneous disease marked by the dysregulation of
cancer driver genes historically classified as oncogenes or tumour suppressors according to their ability to promote or inhibit tumour development and growth, respectively. Certain genes display both oncogenic and tumour suppressor functions depending on the biological context, and as such have been termed dual-role
cancer driver genes. However, because of their context-dependent behaviour, the tumourigenic mechanism of many dual-role genes is elusive and remains a significant knowledge gap in our effort to understand and treat
cancer.
Inositol polyphosphate 4-phosphatase type II (INPP4B) is an emerging dual-role
cancer driver gene, primarily known for its role as a negative regulator of the
phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. In response to
growth factor stimulation, class I PI3K generates
PtdIns(3,4,5)P3 at the plasma membrane.
PtdIns(3,4,5)P3 can be hydrolysed by
inositol polyphosphate 5-phosphatases to generate
PtdIns(3,4)P2, which, together with
PtdIns(3,4,5)P3, facilitates the activation of AKT to promote cell proliferation, survival, migration, and metabolism.
Phosphatase and
tensin homology on chromosome 10 (PTEN) and INPP4B are
dual-specificity phosphatases that hydrolyse
PtdIns(3,4,5)P3 and
PtdIns(3,4)P2, respectively, and thus negatively regulate PI3K/AKT signalling. PTEN is a bona fide tumour suppressor that is frequently lost in human tumours. INPP4B was initially characterised as a tumour suppressor akin to PTEN, and has been implicated as such in a number of
cancers, including prostate, thyroid, and basal-like breast
cancers. However, evidence has since emerged revealing INPP4B as a paradoxical oncogene in several
malignancies, with increased INPP4B expression reported in AML,
melanoma and
colon cancers among others. Although the tumour suppressive function of INPP4B has been mostly ascribed to its ability to negatively regulate PI3K/AKT signalling, its oncogenic function remains less clear, with proposed mechanisms including promotion of PtdIns(3)P-dependent SGK3 signalling, inhibition of PTEN-dependent AKT activation, and enhancing DNA repair mechanisms to confer chemoresistance. Nevertheless, research is ongoing to identify the factors that dictate the tumourigenic output of INPP4B in different human
cancers. In this review we discuss the dualistic role that INPP4B plays in the context of
cancer development, progression and treatment, drawing comparisons to PTEN to explore how their similarities and, importantly, their differences may account for their diverging roles in tumourigenesis.