Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0019204 (
hepatocellular carcinoma
)
71,386
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rationale:
Hepatocellular carcinoma
(
HCC
) is one of the most lethal cancers, and few molecularly targeted anticancer therapies have been developed to treat it. Thus, the identification of new therapeutic targets is urgent. Metabolic reprogramming is an important hallmark of cancer. However, how ubiquitin ligases are involved in the regulation of cancer metabolism remains poorly understood.
Methods:
RT-PCR, western blot and IHC were used to determine
ZFP91
expression. RNAi, cell proliferation, colony formation and transwell assays were used to determine the
in vitro
functions of
ZFP91
. Mouse xenograft models were used to study the
in vivo
effects of
ZFP91
. Co-IP together with mass spectrometry or western blot was utilized to investigate protein-protein interaction. Ubiquitination was analyzed using IP together with western blot. RNA splicing was assessed by using RT-PCR followed by restriction digestion. Lactate production and glucose uptake assays were used to analyze cancer metabolism.
Results:
We identified that an E3 ligase
zinc finger protein 91
(
ZFP91
) suppressed
HCC
metabolic reprogramming, cell proliferation and metastasis
in vitro
and
in vivo
. Mechanistically,
ZFP91
promoted the Lys48-linked ubiquitination of the oncoprotein hnRNP A1 at lysine 8 and proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM splicing, subsequently resulting in higher PKM1 isoform formation and lower PKM2 isoform formation and suppressing
HCC
glucose metabolism reprogramming, cell proliferation and metastasis. Moreover,
HCC
patients with lower levels of
ZFP91
have poorer prognoses, and
ZFP91
is an independent prognostic factor for patients with
HCC
.
Conclusions:
Our study identifies
ZFP91
as a tumor suppressor of hepatocarcinogenesis and
HCC
metabolism reprogramming and proposes it as a novel prognostic biomarker and therapeutic target of
HCC
.
...
PMID:E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing. 3275 63
