PMID- 36133305
OWN - NLM
STAT- MEDLINE
DCOM- 20220923
LR  - 20231105
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 13
DP  - 2022
TI  - Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney 
      tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment 
      of differentiation.
PG  - 932286
LID - 10.3389/fendo.2022.932286 [doi]
LID - 932286
AB  - 2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, 
      including the kidney. The tumorigenesis resulting from overproduced 2HG has been 
      attributed to the ability of 2HG alter gene expression by inhibiting 
      alpha-ketoglutarate (alphaKG)-dependent dioxygenases, including Ten-eleven-Translocation 
      (TET) enzymes. Genes that regulate cellular differentiation are reportedly 
      repressed, blocking differentiation of mesenchymal cells into myocytes, and 
      adipocytes. In this report, the expression of the enzyme responsible for L2HG 
      degradation, L-2HG dehydrogenase (L2HGDH), is knocked down, using lentiviral 
      shRNA, as well as siRNA, in primary cultures of normal Renal Proximal Tubule 
      (RPT) cells. The knockdown (KD) results in increased L-2HG levels, decreased 
      demethylation of 5mC in genomic DNA, and increased methylation of H3 Histones. 
      Consequences include reduced tubulogenesis by RPT cells in matrigel, and reduced 
      expression of molecular markers of differentiation, including membrane 
      transporters as well as HNF1alpha and HNF1beta, which regulate their transcription. 
      These results are consistent with the hypothesis that oncometabolite 2HG blocks 
      RPT differentiation by altering the methylation status of chromatin in a manner 
      that impedes the transcriptional events required for normal differentiation. 
      Presumably, similar alterations are responsible for promoting the expansion of 
      renal cancer stem-cells, increasing their propensity for malignant 
      transformation.
CI  - Copyright (c) 2022 Taub, Mahmoudzadeh, Tennessen and Sudarshan.
FAU - Taub, Mary
AU  - Taub M
AD  - Biochemistry Department, School of Medicine and Biomedical Sciences, State 
      University of New York at Buffalo, Buffalo, NY, United States.
FAU - Mahmoudzadeh, Nader H
AU  - Mahmoudzadeh NH
AD  - Department of Biology, Indiana University, Bloomington, IN, United States.
FAU - Tennessen, Jason M
AU  - Tennessen JM
AD  - Department of Biology, Indiana University, Bloomington, IN, United States.
FAU - Sudarshan, Sunil
AU  - Sudarshan S
AD  - Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 
      United States.
LA  - eng
GR  - R35 GM119557/GM/NIGMS NIH HHS/United States
GR  - R01 CA200653/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220905
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 0 (Chromatin)
RN  - 0 (Glutarates)
RN  - 0 (Histones)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 2889-31-8 (alpha-hydroxyglutarate)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.13.11.- (Dioxygenases)
SB  - IM
MH  - Cell Differentiation/genetics
MH  - Chromatin
MH  - *Dioxygenases/metabolism
MH  - Epigenesis, Genetic
MH  - Glutarates
MH  - *Histones/metabolism
MH  - Ketoglutaric Acids/metabolism
MH  - Kidney/metabolism
MH  - Membrane Transport Proteins/metabolism
MH  - Oxidoreductases/metabolism
MH  - RNA, Small Interfering
PMC - PMC9483015
OTO - NOTNLM
OT  - L-2-Hydroxyglutarate
OT  - differentiation
OT  - matrigel (MA)
OT  - proximal tubule
OT  - renal cell carcinoma
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/23 06:00
MHDA- 2022/09/24 06:00
PMCR- 2022/01/01
CRDT- 2022/09/22 03:52
PHST- 2022/04/29 00:00 [received]
PHST- 2022/08/12 00:00 [accepted]
PHST- 2022/09/22 03:52 [entrez]
PHST- 2022/09/23 06:00 [pubmed]
PHST- 2022/09/24 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2022.932286 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2022 Sep 5;13:932286. doi: 
      10.3389/fendo.2022.932286. eCollection 2022.