Inhibition of protein phosphatase 2A (PP2A) activity has been identified as a prerequisite for the transformation of human cells. The protein, designated Cancerous Inhibitor of PP2A (CIP2A, p90 Autoantigen), interacts directly with the oncogenic transcription factor c-Myc, inhibits PP2A activity toward c-Myc serine 62 (S62), and thereby prevents c-Myc proteolytic degradation. In addition to its function in c-Myc stabilization, p90 Autoantigen promotes anchorage-independent cell growth and in vivo tumor formation. The oncogenic activity of p90 Autoantigen is demonstrated by transformation of human cells by overexpression of p90 Autoantigen. Importantly, p90 Autoantigen is overexpressed in two common human malignancies, head and neck squamous cell carcinoma (HNSCC) and colon cancer.