KLF17 attenuates estrogen receptor α-mediated signaling by impeding ERα function on chromatin and determines response to endocrine therapy.
Luminal-like breast cancer expressing estrogen receptor α (ERα) is among the aggressive breast tumor subtypes and shows poor prognosis. KLF17 plays a key role in breast cancer inhibition. However, the underlying mechanisms by which KLF17 control breast cancer progression remains unknown. Here, we show that KLF17 antagonizes ERα-dependent signaling to suppress breast cancer progression. KLF17 alters ERα-binding pattern throughout the genome and co-localizes with ERα on chromatin. Mechanistically, KLF17 forms a complex with ERα that interferes with ERα binding on chromatin and thereby attenuates ERα-dependent pathway. KLF17 increases the methylation status of ERE target promoters by recruiting transcriptional corepressor N-CoR/HDAC1 complex and prevents RNA polymerase II binding to suppress ERα-dependent transcriptional activation. Importantly, KLF17 preoccupies a subset of ERE target gene promoters and inhibits interaction of ERα with chromatin. Conversely, estrogen signaling suppresses KLF17 transcription via ERα/HDAC1-dependent mechanism. KLF17 expression negatively correlates with ERα target genes in multiple breast cancer samples. Enhanced KLF17 expression sensitizes ERα-positive breast cancer cells to endocrine therapy. KLF17 expression is downregulated in luminal breast cancer subtypes and is associated with poor survival rates in breast cancer patients. Taken together, these results indicate that KLF17-ERα interaction plays a potential role in inhibition of ERα-dependent breast cancer progression and suggests an improved strategy for treatment of ERα-positive breast cancer patients.
Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Hayatabad, Sector F-5, Phase VI, Peshawar, K.P.K, Pakistan; Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, People's Republic of China. Electronic address: amjad_486@yahoo.com.
Amjad
A
Ali
Faculty of Pharmacy, Department of Pharmaceutical Botany, Iuliu Haţieganu University of Medicine and Pharmacy, 23 Gheorghe Marinescu street, Cluj-Napoca, Romania.
Irina
I
Ielciu
Pharmacology Department, Faculty of Medicine, King AbdulAziz University, Jeddah, Saudi Arabia.
Huda Mohammad
HM
Alkreathy
Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Hayatabad, Sector F-5, Phase VI, Peshawar, K.P.K, Pakistan.
Abid Ali
AA
Khan
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002843:Chromatin / Q000378:metabolism*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C510638:KLF17 protein, human; D014157:Transcription Factors
Breast cancer; Endocrine therapy; Estrogen receptor α; HDAC1; KLF17; p300