PMID- 35102251
OWN - NLM
STAT- MEDLINE
DCOM- 20220419
LR  - 20230120
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 41
IP  - 12
DP  - 2022 Mar
TI  - The ubiquitin E3 ligase ARIH1 regulates hnRNP E1 protein stability, EMT and 
      breast cancer progression.
PG  - 1679-1690
LID - 10.1038/s41388-022-02199-9 [doi]
AB  - The epithelial to mesenchymal transition (EMT), a process that is aberrantly 
      activated in cancer and facilitates metastasis to distant organs, requires 
      coordinated transcriptional and post-transcriptional control of gene expression. 
      The tumor-suppressive RNA binding protein, hnRNP-E1, regulates splicing and 
      translation of EMT-associated transcripts and it is thought that it plays a major 
      role in the control of epithelial cell plasticity during cancer progression. We 
      have utilized yeast 2 hybrid screening to identify novel hnRNP-E1 interactors 
      that play a role in regulating hnRNP-E1; this approach led to the identification 
      of the E3 ubiquitin ligase ARIH1. Here, we demonstrate that hnRNP-E1 protein 
      stability is increased upon ARIH1 silencing, whereas, overexpression of ARIH1 
      leads to a reduction in hnRNP-E1. Reduced ubiquitination of hnRNP-E1 detected in 
      ARIH1 knockdown (KD) cells compared to control suggests a role for ARIH1 in 
      hnRNP-E1 degradation. The identification of hnRNP-E1 as a candidate substrate of 
      ARIH1 led to the characterization of a novel function for this ubiquitin ligase 
      in EMT induction and cancer progression. We demonstrate a delayed induction of 
      EMT and reduced invasion in mammary epithelial cells silenced for ARIH1. 
      Conversely, ARIH1 overexpression promoted EMT induction and invasion. ARIH1 
      silencing in breast cancer cells significantly attenuated cancer cell stemness in 
      vitro and tumor formation in vivo. Finally, we utilized miniTurboID proximity 
      labeling to identify novel ARIH1 interactors that may contribute to ARIH1's 
      function in EMT induction and cancer progression.
CI  - (c) 2022. The Author(s).
FAU - Howley, Breege V
AU  - Howley BV
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA.
FAU - Mohanty, Bidyut
AU  - Mohanty B
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA.
FAU - Dalton, Annamarie
AU  - Dalton A
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA.
FAU - Grelet, Simon
AU  - Grelet S
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Department of Biochemistry and Molecular Biology, Mitchell Cancer Institute, 
      University of South Alabama, Mobile, AL, USA.
FAU - Karam, Joseph
AU  - Karam J
AUID- ORCID: 0000-0002-4536-7362
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA.
FAU - Dincman, Toros
AU  - Dincman T
AD  - Department of Medicine, Medical University of South Carolina, Charleston, SC, 
      USA.
FAU - Howe, Philip H
AU  - Howe PH
AUID- ORCID: 0000-0002-1358-1313
AD  - Department of Biochemistry and Molecular Biology, Medical University of South 
      Carolina, Charleston, SC, USA. howep@musc.edu.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA. howep@musc.edu.
LA  - eng
GR  - KL2 TR001452/TR/NCATS NIH HHS/United States
GR  - R01 CA154663/CA/NCI NIH HHS/United States
GR  - UL1 TR001450/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220131
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Heterogeneous-Nuclear Ribonucleoproteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (ARIH1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - *Breast Neoplasms/genetics
MH  - Cell Line, Tumor
MH  - *Epithelial-Mesenchymal Transition/genetics
MH  - Female
MH  - Heterogeneous-Nuclear Ribonucleoproteins/genetics
MH  - Humans
MH  - Protein Stability
MH  - RNA-Binding Proteins/metabolism
MH  - Ubiquitin/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
PMC - PMC8933277
MID - NIHMS1772820
COIS- The authors declare no competing interests.
EDAT- 2022/02/02 06:00
MHDA- 2022/04/20 06:00
PMCR- 2022/01/31
CRDT- 2022/02/01 06:08
PHST- 2020/12/03 00:00 [received]
PHST- 2022/01/18 00:00 [accepted]
PHST- 2022/01/03 00:00 [revised]
PHST- 2022/02/02 06:00 [pubmed]
PHST- 2022/04/20 06:00 [medline]
PHST- 2022/02/01 06:08 [entrez]
PHST- 2022/01/31 00:00 [pmc-release]
AID - 10.1038/s41388-022-02199-9 [pii]
AID - 2199 [pii]
AID - 10.1038/s41388-022-02199-9 [doi]
PST - ppublish
SO  - Oncogene. 2022 Mar;41(12):1679-1690. doi: 10.1038/s41388-022-02199-9. Epub 2022 
      Jan 31.