Estrogen receptor alph (ERα) is implicated in the initiation andprogression of breast cancer and its transcription depends on themodulation of epigenetic changes at target gene promoters viacoregulators. There is a critical need to understand the molecularmechanism(s) by which deregulation of epigenetic changes occursduring breast cancer progression. The ERα coregulator PELP1plays an important role in ERa signaling and is a proto-oncogenewith aberrant expression in breast cancer. PELP1 interactswith histones and may be a reader of chromatin modifications. We profiled PELP1's epigenetic interactome using a histonepeptide array. Our results show that PELP1 recognizes histonesmodified by arginine and lysine dimethylation. PELP1 functionallyinteracts with the arginine methyltransferase CARM1 andtheir interaction is enhanced by ERa. PELP1-CARM1 interactions synergistically enhance ERα transactivation. Chromatin immuno precipitation assays revealed that PELP1 alters histone H3 arginine methylation status at ERα target gene promoters. Pharmacological inhibition or small interfering RNA knockdownof CARM1 substantially reduced PELP1 oncogenic functions. The critical role of PELP1 status in modulating arginine methylationstatus was also observed through in vivo studies where PELP1 knockdown mediated decreased tumorigenesis correlatedwith decreased arginine dimethylation. Further, immunohistochemicalanalysis of human breast tumor tissues revealed cooverexpressionof PELP1 and CARM1 in a subset of ERα-positivebreast tumors. Our findings show PELP1 is a reader of histonearginine methyl modifications and deregulation promotes tumorproliferation via epigenetic alterations at ERα target promoters. Targeting these epigenetic alterations through inhibition of PELP1 and the arginine methyltransferases could be a promisingcancer therapeutic.
ASJC Scopus subject areas
- Cancer Research