The interplay between HPIP and casein kinase 1α promotes renal cell carcinoma growth and metastasis via activation of mTOR pathway

Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP) was shown to be crucial during the development and progression of a variety of tumors. However, the role of HPIP in renal cell carcinoma (RCC) is unknown. Here we report that HPIP is upregulated in most RCC patients, positively correlates with tumor size, high Fuhrman grade and preoperative metastasis, and predicts poor clinical outcomes. Mechanistically, we identified casein kinase 1 alpha (CK1 alpha), a critical regulator of tumorigenesis and metastasis, as a novel HPIP-interacting protein. HPIP facilitates RCC cell growth, migration, invasion and epithelial-mesenchymal transition depending on its interaction with CK1 alpha. Activation of mammalian target of rapamycin pathways by HPIP is partly dependent on CK1 alpha and is required for HPIP modulation of RCC cell proliferation and migration. HPIP knockdown suppresses renal tumor growth and metastasis in nude mice through CK1 alpha. Moreover, expression of CK1 alpha is positively correlated with HPIP in RCC samples, and also predicts poor clinical outcome-like expression of HPIP. Taken together, our data demonstrate the critical regulatory role of the HPIP-CK1 alpha interaction in RCC, and suggest that HPIP and CK1 alpha may be potential targets for RCC therapy.