Title: ERR-SET7/9 interaction : molecular features and pathological consequences on cancer aggressiveness
Directors: Jean-Marc VANACKER & Jiwen LI
Discipline: Life Sciences
Status: Incubating Project
Starting date: 2015
Supervision
Summary
Joint project between JM Vanacker’s lab, ENS Lyon and J. Wong’s lab, ECNU
High expression of the ERRα orphan nuclear receptor is globally associated with a poor prognosis in tumors including those of the breast. In cancer cells, ERRα enhances the expression of genes involved in tumor progression (proliferation, migration, angiogenesis, resistance to hypoxia…). However the mechanism leading to dysregulated ERRα expression in tumors have not been investigated, and the mechanisms through which ERRα regulates the expression of its target genes are unclear. Given that ERRs have no identified natural ligand, most if not all of their transcriptional activities depend on the interaction with co-modulatory proteins, such as members of the PGC-1 co-activator family. On one hand, the expression of ERRα is autoregulated in a PGC-1α-dependent manner; on the other hand, ERRα, which is a weak activator of transcription, can be transformed to a stronger transcriptional activator when PGC-1α is highly expressed. However co-activation by PGC-1 co-activator mainly leads ERRα to activate a “metabolic” transcription program, which is not related to the other cancer functions of the receptor. Recent study showed that the activities of ERRs are also regulated, at least in part, through post-translational modifications. Indeed phosphorylation-dependent sumoylation as well as acetylation negatively affect the activities of the receptor. Taken together, we hypothesize that other modifications such as Lys methylation could occur that affect ERRα transcriptional activity. Recently JM Vanacker’s group showed that i- ERRα transcriptional activity is regulated by the LSD1 histone demethylase, ii- the Set7/9 methyltransferase protects ERRα from degradation, in a manner that depends on Set7/9’s enzymatic activity, suggesting that Set7/9 methylates ERRα, iii- Set7/9 is necessary to ERRα transcriptional activities. Preliminary data also have identified a few common (ERRα and Set7/9) target genes, but this needs to be analyzed at the whole genome level. The expression of Set7/9 in tumors has not been published but preliminary IHC results show that Set7/9 is strongly expressed in breast tumors as compared to normal tissue. Altogether this suggests that ERRα and Set7/9 also form a co-regulatory network that could be involved in cancer progression. Identifying this network as well as its physiopathological outcomes is the purpose of the present project.
J. Wong’s laboratory focuses on epigenetic regulation, including DNA methylation and histone modification. Accumulating evidence showed that lysine methylation decorates both histone proteins and non-histones. Set7/9, which is a monomethyltransferase acting on H3K4, predominately found in active chromatin, is also involved in the non-histone protein methylation (such as p53 or DNMT1), an activity which impacts on gene transcription, protein stability and subcellular location.
The current research plan includes the analysis of i- the methylation of ERRα by the Set7/9 methyltransferase; ii- the regulation of the transcriptional activity of ERRα by Set7/9-mediated methylation/stability; iii- the functional outcomes of the Set7/9-mediated methylation/stability on cancer progression.