PMID- 33076532
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20210623
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 10
IP  - 10
DP  - 2020 Oct 15
TI  - Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human 
      Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide.
LID - 10.3390/biom10101450 [doi]
LID - 1450
AB  - HMGB1 and HMGB2 proteins are abundantly expressed in human embryonic stem cells 
      (hESCs) and hESC-derived progenitor cells (neuroectodermal cells, hNECs), though 
      their functional roles in pluripotency and the mechanisms underlying their 
      differentiation in response to the anticancer drug etoposide remain to be 
      elucidated. Here, we show that HMGB1 and/or HMGB2 knockdown (KD) by shRNA in 
      hESCs did not affect the cell stemness/pluripotency regardless of etoposide 
      treatments, while in hESC-derived neuroectodermal cells, treatment resulted in 
      differential effects on cell survival and the generation of rosette structures. 
      The objective of this work was to determine whether HMGB1/2 proteins could 
      modulate the sensitivity of hESCs and hESC-derived progenitor cells (hNECs) to 
      etoposide. We observed that HMGB1 KD knockdown (KD) and, to a lesser extent, 
      HMGB2 KD enhanced the sensitivity of hESCs to etoposide. Enhanced accumulation of 
      53BP1 on telomeres was detected by confocal microscopy in both untreated and 
      etoposide-treated HMGB1 KD hESCs and hNECs, indicating that the loss of HMGB1 
      could destabilize telomeres. On the other hand, decreased accumulation of 53BP1 
      on telomeres in etoposide-treated HMGB2 KD hESCs (but not in HMGB2 KD hNECs) 
      suggested that the loss of HMGB2 promoted the stability of telomeres. Etoposide 
      treatment of hESCs resulted in a significant enhancement of telomerase activity, 
      with the highest increase observed in the HMGB2 KD cells. Interestingly, no 
      changes in telomerase activity were found in etoposide-treated control hNECs, but 
      HMGB2 KD (unlike HMGB1 KD) markedly decreased telomerase activity in these cells. 
      Changes in telomerase activity in the etoposide-treated HMGB2 KD hESCs or hNECs 
      coincided with the appearance of DNA damage markers and could already be observed 
      before the onset of apoptosis. Collectively, we have demonstrated that HMGB1 or 
      HMGB2 differentially modulate the impact of etoposide treatment on human 
      embryonic stem cells and their progenitor cells, suggesting possible strategies 
      for the enhancement of the efficacy of this anticancer drug.
FAU - Bagherpoor, Alireza Jian
AU  - Bagherpoor AJ
AD  - Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 
      00 Brno, Czech Republic.
FAU - Kucirek, Martin
AU  - Kucirek M
AD  - Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 
      00 Brno, Czech Republic.
FAU - Fedr, Radek
AU  - Fedr R
AD  - Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 
      00 Brno, Czech Republic.
FAU - Sani, Soodabeh Abbasi
AU  - Sani SA
AD  - Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 
      00 Brno, Czech Republic.
FAU - Stros, Michal
AU  - Stros M
AD  - Institute of Biophysics of the Czech Academy of Sciences, Kralovopolska 135, 612 
      00 Brno, Czech Republic.
LA  - eng
GR  - NU20-08-00106/Ministry of Health and Education of the Czech 
      Republic/International
GR  - P305-15-01354S/Grant Agency of the Czech Republic/International
GR  - IBP CAS 68081707/Internal Research Support Program of the Institute of Biophysics 
      Brno/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201015
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HMGB1 Protein)
RN  - 0 (HMGB1 protein, human)
RN  - 0 (HMGB2 Protein)
RN  - 0 (RNA, Small Interfering)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - EC 2.7.7.49 (Telomerase)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Differentiation/genetics
MH  - Etoposide/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/genetics
MH  - HMGB1 Protein/antagonists & inhibitors/*genetics
MH  - HMGB2 Protein/antagonists & inhibitors/*genetics
MH  - Human Embryonic Stem Cells
MH  - Humans
MH  - Neoplasms/*drug therapy/genetics/pathology
MH  - Neoplastic Stem Cells/drug effects/metabolism
MH  - RNA, Small Interfering
MH  - Stem Cells/drug effects
MH  - Telomerase/genetics
PMC - PMC7602880
OTO - NOTNLM
OT  - HMGB1 and HMGB2
OT  - apoptosis
OT  - etoposide
OT  - human embryonic stem cells
OT  - neuroectodermal cells
OT  - telomerase
COIS- The authors declare no conflict of interest
EDAT- 2020/10/21 06:00
MHDA- 2021/06/24 06:00
PMCR- 2020/10/01
CRDT- 2020/10/20 01:03
PHST- 2020/09/14 00:00 [received]
PHST- 2020/10/09 00:00 [revised]
PHST- 2020/10/09 00:00 [accepted]
PHST- 2020/10/20 01:03 [entrez]
PHST- 2020/10/21 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2020/10/01 00:00 [pmc-release]
AID - biom10101450 [pii]
AID - biomolecules-10-01450 [pii]
AID - 10.3390/biom10101450 [doi]
PST - epublish
SO  - Biomolecules. 2020 Oct 15;10(10):1450. doi: 10.3390/biom10101450.