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

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Abstract

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 IIα (MAT IIα) and promotes its proteasomal degradation through the ubiquitylation-mediated pathway. MAT IIα 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 IIα exhaustion and growth arrest in colorectal cancer (CRC) cells. Further results from human CRC samples display an inverse correlation between CUL3 and MAT IIα protein levels. Our observations reveal a novel role of CUL3 in regulating cell proliferation by controlling the stability of MAT IIα.

Methionine adenosyltransferase IIα (MAT IIα) is a key enzyme in methionine metabolism and is associated with uncontrolled cell proliferation and tumorigenesis. Jian Wang et al. report that the scaffold protein Cullin 3 (CUL3), which forms part of a multi-subunit E3 ubiquitin ligase complex, targets MAT IIα for ubiquitin-mediated proteasomal degradation. Depletion of CUL3 prevents folate deprivation-induced MAT IIα degradation and growth arrest in colorectal cancer cells. The authors also found an inverse correlation between CUL3 and MAT IIα levels in primary human colorectal cancer samples. This work suggests a role for CUL3 in regulating cell proliferation by controlling the stability of MAT IIα.

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