The tumor suppressive role of PRMT6 in regulating the pathogenesis of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The overall 5-year survival rate of HCC patients remains at a dismal 15% due to late diagnosis, metastasis and frequent tumor relapse. The presence of cancer stem cells (CSCs) has been proposed to account partly for the challenge of treating HCC. Our group has previously identified CD133 as a functional CSC marker of HCC. By adopting a PCR array encompassing diverse human chromatin modifiers, protein arginine methyltransferase 6 (PRMT6) was found to be differentially down-regulated in CD133+ human HCC cells. 55.8% (43/77) of clinical HCC tumor tissues showed down-regulated PRMT6 expression and patients with reduced PRMT6 expression were at significant risk of disrupted tumor encapsulation and manifested vascular invasion. An antagonistic relationship between PRMT6 and CD133 was observed in HCC cells, while modulation of PRMT6 led to an inversely altered CD133 expression. PRMT6 knockdown in liver cancer cells induced morphological alterations, where extensive cytoplasmic stretching and filopodia-like projections were observed. Moreover, PRMT6 regulated cancer and stem cell-like properties in vitro and in vivo including proliferation, colony formation, invasion, migration, angiogenesis, self-renewal, chemo-sensitivity and tumor initiation. In addition, stable knockdown of CD133 in HCC cells did not alter PRMT6 expression levels, which suggested that PRMT6 is potentially functioning upstream of CD133. Ongoing studies are in progress to delineate the underlying mechanisms by which PRMT6 suppress HCC.