PMID- 34771469
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211118
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 21
DP  - 2021 Oct 22
TI  - TPH1 and 5-HT(7) Receptor Overexpression Leading to Gemcitabine-Resistance 
      Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal 
      Adenocarcinoma.
LID - 10.3390/cancers13215305 [doi]
LID - 5305
AB  - In the present study, we investigated the regulatory mechanisms underlying 
      overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT(7), in relation 
      to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 
      and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease 
      in CSCs and recovery from gemcitabine resistance, while preconditioning of less 
      aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased 
      expression of EZH2, TPH1, and 5-HT(7). Such effects of the gene KD and 5-HT 
      treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 
      KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling 
      pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by 
      downregulation of TPH1 and 5-HT(7). Co-immunoprecipation with EZH2 and pan-methyl 
      lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for 
      binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. 
      Furthermore, the inhibitor of EZH2, TPH1, or 5-HT(7) effectively regressed 
      pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results 
      revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical 
      action of EZH2 allowed the expression of TPH1-5-HT(7) axis leading to gemcitabine 
      resistance and CSC population in PDAC.
FAU - Chaudhary, Prakash
AU  - Chaudhary P
AD  - College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
FAU - Guragain, Diwakar
AU  - Guragain D
AD  - College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
FAU - Chang, Jae-Hoon
AU  - Chang JH
AUID- ORCID: 0000-0002-1001-6570
AD  - College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
FAU - Kim, Jung-Ae
AU  - Kim JA
AUID- ORCID: 0000-0002-0824-8532
AD  - College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
LA  - eng
GR  - NRF-2020R1A2C2005690 and NRF-2017R1E1A1A01073590/National Research Foundation of 
      Korea/
PT  - Journal Article
DEP - 20211022
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8582390
OTO - NOTNLM
OT  - 5-HT7
OT  - Enhancer of zeste homolog 2
OT  - cancer stem cells
OT  - gemcitabine-resistance
OT  - pancreatic ductal adenocarcinoma
OT  - tryptophan hydroxylase 1
COIS- The authors declare that they have no competing interests.
EDAT- 2021/11/14 06:00
MHDA- 2021/11/14 06:01
PMCR- 2021/10/22
CRDT- 2021/11/13 01:14
PHST- 2021/09/14 00:00 [received]
PHST- 2021/10/20 00:00 [revised]
PHST- 2021/10/20 00:00 [accepted]
PHST- 2021/11/13 01:14 [entrez]
PHST- 2021/11/14 06:00 [pubmed]
PHST- 2021/11/14 06:01 [medline]
PHST- 2021/10/22 00:00 [pmc-release]
AID - cancers13215305 [pii]
AID - cancers-13-05305 [pii]
AID - 10.3390/cancers13215305 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 Oct 22;13(21):5305. doi: 10.3390/cancers13215305.