PMID- 28604753
OWN - NLM
STAT- MEDLINE
DCOM- 20171024
LR  - 20220129
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 42
DP  - 2017 Oct 19
TI  - let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell 
      migration by targeting multiple components of the H2B deubiquitylation machinery.
PG  - 5819-5828
LID - 10.1038/onc.2017.187 [doi]
AB  - Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 
      complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences 
      many aspects of chromatin function, including transcription regulation and DNA 
      repair. Cancer cells often display reduced levels of H2Bub1, and this reduction 
      may contribute to cancer progression. The let-7 family of microRNAs (miRNAs) 
      comprises multiple members with reported tumor-suppressive features, whose 
      expression is frequently downregulated in cancer. We now report that let-7b and 
      let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b 
      and let-7c in a variety of non-transformed and cancer-derived cell lines results 
      in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is 
      achieved through targeting of multiple mRNAs, coding for distinct components of 
      the H2B deubiquitylation machinery. Specifically, let-7b and let-7c bind directly 
      and inhibit the mRNAs encoding the DUBs USP42 and USP44, and also the mRNA 
      encoding the adapter protein ATXN7L3, which is part of the DUB module of the SAGA 
      complex. RNF20 knockdown (KD) strongly reduces H2Bub1 levels and increases the 
      migration of non-transformed mammary epithelial cells and breast cancer-derived 
      cells. Remarkably, overexpression of let-7b, which partly counteracts the effect 
      of RNF20 KD on H2Bub1 levels, also reverses the pro-migratory effect of RNF20 KD. 
      Likewise, ATXN7L3 KD also increases H2Bub1 levels and reduces cell migration, and 
      this anti-migratory effect is abolished by simultaneous KD of RNF20. Together, 
      our findings uncover a novel function of let-7 miRNAs as regulators of H2B 
      ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert 
      their tumor-suppressive effects.
FAU - Spolverini, A
AU  - Spolverini A
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Fuchs, G
AU  - Fuchs G
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Bublik, D R
AU  - Bublik DR
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Oren, M
AU  - Oren M
AD  - Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 
      Israel.
LA  - eng
GR  - 293438/ERC_/European Research Council/International
PT  - Journal Article
DEP - 20170612
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (ATXN7L3 protein, human)
RN  - 0 (Histones)
RN  - 0 (MicroRNAs)
RN  - 0 (Transcription Factors)
RN  - 0 (USP42 protein, human)
RN  - 0 (mirnlet7 microRNA, human)
RN  - EC 2.3.2.27 (RNF20 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.4.19.12 (USP44 protein, human)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - EC 3.4.19.12 (Ubiquitin-Specific Proteases)
SB  - IM
MH  - Breast Neoplasms/genetics/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cell Movement/*physiology
MH  - Cell Proliferation
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Histones/*metabolism
MH  - Humans
MH  - Lung Neoplasms/genetics/metabolism/*pathology
MH  - MicroRNAs/genetics/*metabolism
MH  - Signal Transduction
MH  - Thiolester Hydrolases/metabolism
MH  - Transcription Factors/metabolism
MH  - Ubiquitin Thiolesterase
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Ubiquitin-Specific Proteases/metabolism
MH  - Ubiquitination
PMC - PMC5600258
MID - EMS72775
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2017/06/13 06:00
MHDA- 2017/10/25 06:00
PMCR- 2017/12/12
CRDT- 2017/06/13 06:00
PHST- 2016/11/18 00:00 [received]
PHST- 2017/04/18 00:00 [revised]
PHST- 2017/05/10 00:00 [accepted]
PHST- 2017/06/13 06:00 [pubmed]
PHST- 2017/10/25 06:00 [medline]
PHST- 2017/06/13 06:00 [entrez]
PHST- 2017/12/12 00:00 [pmc-release]
AID - onc2017187 [pii]
AID - 10.1038/onc.2017.187 [doi]
PST - ppublish
SO  - Oncogene. 2017 Oct 19;36(42):5819-5828. doi: 10.1038/onc.2017.187. Epub 2017 Jun 
      12.