GSTZ 1‐1 Deficiency Activates NRF 2/ IGF 1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone

Abstract

The IGF 1R signaling is important in the malignant progression of cancer. However, overexpression of IGF 1R has not been properly assessed in HCC . Here, we revealed that GSTZ 1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC , and its expression was negatively correlated with IGF 1R. Mechanistically, GSTZ 1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP 1, and NRF 2 activation, thus promoting IGF 1R transcription by recruiting SP 1 to its promoter. Moreover, inhibition of IGF 1R or NRF 2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo . These findings establish succinylacetone as an oncometabolite, and GSTZ 1‐1 as an important tumor suppressor by inhibiting NRF 2/ IGF 1R axis in HCC . Targeting NRF 2 or IGF 1R may be a promising treatment approach for this subset HCC .

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

“…GSTZ1 expression is downregulated in HCC. [63] GSTZ1 expression is downregulated in tumor tissue compared to adjacent normal tissue and correlates with poor prognosis. [250] High GSTP1 expression correlates with better survival and smaller tumor size.…”

“…Its upregulation was suggested as a protection mechanism of hepatocellular carcinoma (HCC)-initiating cells in the oxidative stress hostile environment that promotes HCC carcinogenesis [ 61 ], as well as anticancer drug tolerance in tumor regions positive for the hepatitis C virus [ 62 ]. The alkylation of KEAP1 by succinylacetone [ 63 ] or the hypermethylation of the KEAP1 promoter region may lead to NRF2 activation. For instance, the tumor-specific hypermethylation of the KEAP1 promoter region was suggested as a specific feature of a clear cell renal carcinoma [ 64 ].…”

“…In that regard, GPX1, GPX3, and GPX7 expression were found to be decreased [ 144 , 240 , 241 , 242 , 243 ] in tumor tissues, while the expression of GPX2 and GPX4 was found to be upregulated [ 144 , 146 , 244 , 245 , 246 , 247 ]. In addition, GSTA1, GSTM1, and GSTZ1 are reported to be downregulated in tumor tissue and can correlate with a poor prognosis [ 63 , 248 , 249 , 250 , 251 ], while GSTT1, GSTO1, and GSTK1 are mostly reported to be upregulated in tumor tissue compared to the normal surrounding tissue [ 252 , 253 ]. The expression level of GSTP1 in tumor tissue is controversial [ 144 , 253 , 254 , 255 ], and its involvement in tumorigenesis could at least in part depend on its hypermethylation [ 256 , 257 , 258 , 259 , 260 ].…”

Prognosis prediction of hepatocellular carcinoma after surgical resection based on serum metabolic profiling from gas chromatography-mass spectrometry

“…Therefore, the abnormal increase of phenylalanine and tyrosine may be related to the occurrence and development of HCC. Glutathione Stransferase zeta 1 (GSTZ1-1), the enzyme in phenylalanine/ tyrosine catabolism, was downregulated in HCC, and low expression of GSTZ1-1 was proved to be correlated with poor prognosis of HCC patients [22], which indicated that phenylalanine/tyrosine catabolism has a potential relevance to the prognosis of HCC. Additionally, it was reported that galactose in the urine of patients with HCC was significantly upregulated [23].…”

NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis

“…Loss of SWI/SNF chromatin-remodeling complex activity also increases NRF2 activity [170]. Moreover, the ability of KEAP1 to repress NRF2 can be inhibited by oncometabolites such as fumarate [171,172], methylglyoxal [173] and succinylacetone [174], or NRF2 can be upregulated by overexpression of proteins that contain ETGE, or ETGE-like, motifs resulting in NRF2 being out-competed for binding to KEAP1; examples include iASPP, CHD6, DPP3, FAM129B, IKKβ, LAMA1, MCM3, SQSTM1/p62, PALB2, PGAM5 and WTX [175].…”