Proteins make them ideal therapeutic targets, and clinical and in vitro evidence is accumulating that MAGE I expression contributes to cancer chemoresistance and growth, cell survival, and metastasis. We and others have previously shown that common functions of MAGE are to bind to KAP1 and suppress p53 but the biochemical functions of MAGE I proteins remain incompletely understood. In the present work we demonstrate that MAGE I expression can regulate ZNF382, an important KZNF tumor suppressor, and can affect the ability of ZNF382 and KAP1 to bind and regulate a downstream target, the ID1 oncogene. MAGE expression suppresses ZNF382 function, decreasing KAP1 binding to ID1 and promoting ID1 expression, in line with previously observed pro-oncogenic effects of MAGE I. We also show MAGE I can affect KAP1 binding to the Ki67 gene, with seemingly opposite effects, including increased KAP1 binding, increased chromatin compaction, and decreased gene expression. Additionally, MAGE-C2L152A,L153A fails to regulate gene expression, indicating that proper binding ASP1517 between MAGE I and KAP1 is required for MAGE I regulation of gene expression. ZNF382 is a tumor suppressor that is ubiquitously expressed in normal tissues, where it recruits KAP1 and causes chromatin compaction and suppression of several oncogenes including ID1. Expression of ZNF382 has been reported to be lost in cancers due to gene deletion or hypermethylation, but ZNF382 expression and tumor suppression are expected in hypomethylated states. Hypomethylated states support MAGE I expression, and our data show unequivocally that MAGE I can suppress ZNF382 function, thereby relieving repression of ZNF382 downstream targets and inducing oncogene expression. Thus, MAGE I expression offers a mechanism for ZNF382 suppression and oncogene activation in the absence of DNA hypermethylation or ZNF382 gene deletion. It has been shown that MAGE I enhances E3 ubiquitination of p53 by increasing KAP1 ubiquitin E3 ligase activity through recruitment and/or stabilization of E3 ubiquitin-conjugating cascades. Our data show that MAGE I induces ubiquitination and degradation of ZNF382 and that binding of MAGE to KAP1 is required, suggesting that MAGE I can also increase KAP1 ubiquitination of KZNFs. However, other possible mechanisms such as ubiquitin receptor modification or interference with the assembly of the basal transcription apparatus by the ubiquitin moiety itself cannot be completely excluded. While it appears clear that MAGE I can decrease KAP1 binding in the case of the ID1 gene, probably by increasing ubiquitination and degradation of KZNF382, there are at least two other potential mechanisms by which MAGE I could affect KAP1 localization and gene repression. Since both MAGE I and KZNF proteins bind to the KAP1 RBCC region, overlap or close proximity of the KAP1 motifs recognized by MAGE I and KZNFs could result in competition, with decreased KZNF binding to KAP1 leading to decreased KAP1 recruitment to specific sites. Alternatively, MAGE I expression may stabilize binding between KZNFs and KAP1 without increasing ubiquitination, a situation which fits the data observed for Ki67 where mediated by an unknown KZN.