RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer.
Breast cancer subtypes display distinct biological traits that influence their clinical behavior and response to therapy. Recent studies have highlighted the importance of chromatin structure regulators in tumorigenesis. The RNF20-RNF40 E3 ubiquitin ligase complex monoubiquitylates histone H2B to generate H2Bub1, while the deubiquitinase (DUB) USP44 can remove this modification. We found that RNF20 and RNF40 expression and global H2Bub1 are relatively low, and USP44 expression is relatively high, in basal-like breast tumors compared with luminal tumors. Consistent with a tumor-suppressive role, silencing of RNF20 in basal-like breast cancer cells increased their proliferation and migration, and their tumorigenicity and metastatic capacity, partly through upregulation of inflammatory cytokines. In contrast, in luminal breast cancer cells, RNF20 silencing reduced proliferation, migration and tumorigenic and metastatic capacity, and compromised estrogen receptor transcriptional activity, indicating a tumor-promoting role. Notably, the effects of USP44 silencing on proliferation and migration in both cancer subtypes were opposite to those of RNF20 silencing. Hence, RNF20 and H2Bub1 have contrasting roles in distinct breast cancer subtypes, through differential regulation of key transcriptional programs underpinning the distinctive traits of each subtype.
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Ohad
O
Tarcic
Department of Developmental Biology and Cancer Research, Institute for Medical Research - Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Roy Z
RZ
Granit
Molecular Carcinogenesis Group, Department of Histology-Embryology, School of Medicine, University of Athens, Athens, Greece.
Ioannis S
IS
Pateras
Department of Developmental Biology and Cancer Research, Institute for Medical Research - Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Hadas
H
Masury
Department of Pathology, Hadassah Medical Center, Jerusalem, Israel.
Bella
B
Maly
Department of Biological Regulation, The Weizmann Institute, Rehovot, Israel.
Yaara
Y
Zwang
Department of Biological Regulation, The Weizmann Institute, Rehovot, Israel.
Yosef
Y
Yarden
Molecular Carcinogenesis Group, Department of Histology-Embryology, School of Medicine, University of Athens, Athens, Greece.|Biomedical Research Foundation, Academy of Athens, Athens, Greece.|Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Vassilis G
VG
Gorgoulis
Department of Immunology and Cancer Research and Department of Pathology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Eli
E
Pikarsky
Department of Developmental Biology and Cancer Research, Institute for Medical Research - Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Ittai
I
Ben-Porath
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Moshe
M
Oren
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D016207:Cytokines; D006657:Histones; D015850:Interleukin-6; D016328:NF-kappa B; D011960:Receptors, Estrogen; D051996:Transcription Factor RelA; C506646:RNF20 protein, human; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases; C579216:USP44 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases