Grainyhead-Like Protein 2 Regulates the Transcriptional Activity of Estrogen Receptor Alpha Phosphorylated at Serine 118 in Breast Cancer

• Main Author: Reese, Rebecca M
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2022
• Subjects: Cellular biology; Genetics; Molecular biology
• ISBN: 9798834030102

The Grainyhead-like protein family, composed of GRHL1, GRHL2, and GRHL3, are nuclear transcription factors that regulate epithelial differentiation. GRHL2 is characterized as having oncogenic and tumor suppressive roles across many cancers. GRHL2 is also associated with several nuclear hormone receptors, including progesterone receptor (PR), androgen receptor (AR), and more recently, estrogen receptor (ER). ER is expressed in over 70% of breast cancers and is a major therapeutic target. GRHL2 is more highly expressed in ER-positive over ER-negative breast cancers, and studies suggest that GRHL2 modulates ER recruitment to chromatin. GRHL2 is hypothesized to enhance ER-transcriptional activity by recruiting histone modifiers like MLL3 to enhancers, but it can also repress ER-transcriptional activity by suppressing the catalytic activity of the histone acetyltransferase p300. Our group found a specific association of the GRHL2 motif with ER phosphorylated at serine 118 (pS118-ER), a post-translational modification activated by estrogen (E2) that is required for maximal ER-transcriptional activity. As a whole, the mechanisms by which GRHL2 regulates ER-transcriptional activity and, more specifically, pS118-ER transcriptional activity are not well understood. In the work presented here, I take cistromic and transcriptomic approaches to explore the role of GRHL2 in facilitating pS118-ER recruitment to chromatin and downstream transcriptional activity. I find that GRHL2 is critical for maximal pS118-ER chromatin-recruitment, GRHL2 can both enhance and antagonize E2-mediated pS118-ER transcriptional activity, and ER/GRHL2 co-regulated genes are involved in cellular migration. The dual roles of GRHL2 in pS118-ER transcriptional regulation may be due to the pioneering activities of GRHL2 which allow the factor to promote an open chromatin structure and subsequently recruit or modulate coregulators present at a given locus. I also explore the function of a portion of the poorly defined GRHL2 transactivation domain and find a 52 amino acid portion of the domain is important for GRHL2 transactivation activity. These studies further our understanding of the function of GRHL2 in regulating pS118-ER transcriptional activity in breast cancer and provide a basis for future studies to expand our knowledge of the interaction between these two transcription factors.