PMID- 38347590
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240320
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 22
IP  - 1
DP  - 2024 Feb 12
TI  - Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous 
      regulation of Cancer stem cells.
PG  - 119
LID - 10.1186/s12964-024-01512-1 [doi]
LID - 119
AB  - BACKGROUND: Breast cancer cells (BCCs) can remain undetected for decades in 
      dormancy. These quiescent cells are similar to cancer stem cells (CSCs); hence 
      their ability to initiate tertiary metastasis. Dormancy can be regulated by 
      components of the tissue microenvironment such as bone marrow mesenchymal stem 
      cells (MSCs) that release exosomes to dedifferentiate BCCs into CSCs. The 
      exosomes cargo includes histone 3, lysine 4 (H3K4) methyltransferases - KMT2B and 
      KMT2D. A less studied mechanism of CSC maintenance is the process of 
      cell-autonomous regulation, leading us to examine the roles for KMT2B and KMT2D 
      in sustaining CSCs, and their potential as drug targets. METHODS: Use of 
      pharmacological inhibitor of H3K4 (WDR5-0103), knockdown (KD) of KMT2B or KMT2D 
      in BCCs, real time PCR, western blot, response to chemotherapy, RNA-seq, and flow 
      cytometry for circulating markers of CSCs and DNA hydroxylases in BC patients. In 
      vivo studies using a dormancy model studied the effects of KMT2B/D to 
      chemotherapy. RESULTS: H3K4 methyltransferases sustain cell autonomous regulation 
      of CSCs, impart chemoresistance, maintain cycling quiescence, and reduce 
      migration and proliferation of BCCs. In vivo studies validated KMT2's role in 
      dormancy and identified these genes as potential drug targets. DNA methylase 
      (DNMT), predicted within a network with KMT2 to regulate CSCs, was determined to 
      sustain circulating CSC-like in the blood of patients. CONCLUSION: H3K4 
      methyltransferases and DNA methylation mediate cell autonomous regulation to 
      sustain CSC. The findings provide crucial insights into epigenetic regulatory 
      mechanisms underlying BC dormancy with KMT2B and KMT2D as potential therapeutic 
      targets, along with standard care. Stem cell and epigenetic markers in 
      circulating BCCs could monitor treatment response and this could be significant 
      for long BC remission to partly address health disparity.
CI  - (c) 2024. The Author(s).
FAU - Ferrer-Diaz, Alejandra I
AU  - Ferrer-Diaz AI
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA.
AD  - Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA.
FAU - Sinha, Garima
AU  - Sinha G
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA.
AD  - Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA.
FAU - Petryna, Andrew
AU  - Petryna A
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA.
AD  - Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA.
FAU - Gonzalez-Bermejo, Ruth
AU  - Gonzalez-Bermejo R
AD  - University of Puerto Rico, Cayey, PR, Puerto Rico.
FAU - Kenfack, Yannick
AU  - Kenfack Y
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA.
AD  - Rutgers School of Graduate Studies at New Jersey Medical School, Newark, NJ, USA.
FAU - Adetayo, Oluwadamilola
AU  - Adetayo O
AD  - Rutgers School of Dental Medicine, Newark, NJ, USA.
FAU - Patel, Shyam A
AU  - Patel SA
AD  - Division of Hematology and Oncology, Department of Medicine, UMass Memorial 
      Medical Center, UMass Chan Medical School, Worcester, MA, USA.
FAU - Hooda-Nehra, Anupama
AU  - Hooda-Nehra A
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA.
AD  - Rutgers Cancer Institute of New Jersey, Newark, NJ, USA.
FAU - Rameshwar, Pranela
AU  - Rameshwar P
AD  - Department of Medicine - Division of Hematology/Oncology, Rutgers, New Jersey 
      Medical School, Newark, NJ, 07103, USA. rameshwa@njms.rutgers.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20240212
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0 (Histones)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - 9007-49-2 (DNA)
RN  - 0 (WDR5 protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
SB  - IM
MH  - Humans
MH  - *Neoplastic Stem Cells/pathology
MH  - Histones/genetics
MH  - Epigenesis, Genetic
MH  - Methyltransferases/genetics
MH  - DNA
MH  - *Neoplasms/pathology
MH  - Intracellular Signaling Peptides and Proteins/genetics
PMC - PMC10863086
OTO - NOTNLM
OT  - Breast cancer
OT  - Cancer stem cell
OT  - Dormancy
OT  - Epigenome
OT  - Resistance
COIS- The authors declare no competing interests.
EDAT- 2024/02/13 00:42
MHDA- 2024/02/14 12:42
PMCR- 2024/02/12
CRDT- 2024/02/12 23:47
PHST- 2023/12/30 00:00 [received]
PHST- 2024/02/01 00:00 [accepted]
PHST- 2024/02/14 12:42 [medline]
PHST- 2024/02/13 00:42 [pubmed]
PHST- 2024/02/12 23:47 [entrez]
PHST- 2024/02/12 00:00 [pmc-release]
AID - 10.1186/s12964-024-01512-1 [pii]
AID - 1512 [pii]
AID - 10.1186/s12964-024-01512-1 [doi]
PST - epublish
SO  - Cell Commun Signal. 2024 Feb 12;22(1):119. doi: 10.1186/s12964-024-01512-1.