Many common genetic and epigenetic anomalies in colon cancer, such as activating mutations of KRAS, and loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN), converge on activation of PI3K signalling. While PTEN is a well-established tumor suppressor, some 5-phosphatases such as SHIP2 and PIB5PA also play a tumor suppressive role through inhibition of PI3K signaling in a variety of types of cancers. However, the role of 4-phosphatases, in particular INPP4B, in the pathogenesis of colon cancer remains to be defined. We aim to characterize the expression of INPP4B in colon cancer cells and to define its functional significance in the pathogenesis of colon cancer. Our results show that INPP4B expression was commonly upregulated in colon cancer cells, and high INPP4B expression was associated with poor patient survival after surgical excision, knockdown of INPP4B resulted in decreased activation of Akt and SGK3, which led to inhibition of proliferation and survival of colon cancer cells in vitro and retardation in colon cancer xenograft growth in a mouse model. On the other hand, introduction of exogenous INPP4B into normal colon epithelial cells resulted in increased cell proliferation and anchorage-independent growth. The promoting effect of INPP4B on PI3K signalling appeared to be mediated by downregulation of PTEN through its protein phosphatase activity, whearas upregulation of INPP4B was due to a transcriptional increase mediated by Ets-1 in colon cancer cells.
The results define INPP4B as an oncogenic regulator in colon cancer, in contrast to its function as a tumor suppressor in some other tissues, and reveal that INPP4B can regulate PI3K signaling positively or negatively and thus differentially affects cell proliferation and survival in a tissue type-specific manner. Therefore, the role of INPP4B in the development, progression, and responses to treatment of different types (subtypes) of cancers needs to be defined discretely.