Cullin 3 targets methionine adenosyltransferase IIα for ubiquitylation-mediated degradation and regulates colorectal cancer cell proliferation

Cullin 3 (CUL3) serves as a scaffold protein and assembles a large number of ubiquitin ligase complexes. It is involved in multiple cellular processes and plays a potential role in tumor development and progression. In this study, we demonstrate that CUL3 targets methionine adenosyltransferase II alpha (MAT II alpha) and promotes its proteasomal degradation through the ubiquitylation- mediated pathway. MAT II alpha is a key enzyme in methionine metabolism and is associated with uncontrolled cell proliferation in cancer. We presently found that CUL3 down-regulation could rescue folate deprivation- induced MAT II alpha exhaustion and growth arrest in colorectal cancer (CRC) cells. Further results from human CRC samples display an inverse correlation between CUL3 and MAT II alpha protein levels. Our observations reveal a novel role of CUL3 in regulating cell proliferation by controlling the stability of MAT II alpha.