Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma

Abstract

Ayudas para apoyar a grupos de investigación del sistema Universitario Vasco (IT971-16);

Epigenetics in hepatoblastoma

“…In fact, the expression of DNMT1, which is in charge of the maintenance of the DNA methylation pattern during mitosis, has been reported to be upregulated in hepatic fibrosis and HCC [113,114] . It has also been demonstrated that DNMTs are upregulated in others types of cancer such as gastric cancer [115] , prostate cancer [116] , CCA [117] , and pancreatic cancer [118] . Indeed, DNMT1, DNMT3A, and DNMT3B are known to also be upregulated in HB tumors [18,119] .…”

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

“…This sequence of events can be accelerated and enhanced by the chronic administration of the hepatotoxin and carcinogen TAA, which also hastens the emergence of markers of CCA development, as seen above. We recently described that when Jnk ∆hepa mice are treated with a single dose of the carcinogen diethylnitrosamine (DEN), and then chronically challenged with CCl 4 (DEN/CCl 4 model), instead of hepatocellular carcinomas, these animals develop cyst-like structures with molecular features compatible with cholangioma and malignant CCA [ 1 , 17 ], including upregulated expression of NOTCH1, GS and markers of oval cells ( Ck19 , Sox9 , Yap1 mRNA), as well as increased proliferation measured as Pcna mRNA levels ( Supplementary Figure S8A–I ), similar to those observed now in response to TAA. In view of this, and of the recognized risk of CCA development in patients with fibrocystic liver diseases, including CD [ 13 , 31 , 32 ], it was important to provide conclusive evidence of the malignant nature of the lesions developed in these mice.…”

“…However, when subjected to the DEN/CCl 4 challenge (as described in Supplementary Figure S8A ), 22-week-old Jnk ∆hepa mice developed strong activation of the UPR ( Figure 9 B) and a potent cystogenic and fibrogenic response ( Figure 9 C). We recently described that the malignant progression of CCA-like lesions in DEN/CCl 4 treated Jnk ∆hepa mice can be inhibited by the administration of CM272, a novel epigenetic drug that simultaneously targets the histone methyltransferase G9a and DNA-methyltransferase 1 (DNMT1) [ 17 ]. Interestingly, CM272 administration, as described in Supplementary Figure S9A , markedly reduced the expression of UPR effectors ( Figure 9 B) and significantly attenuated the fibrogenic and cystogenic responses ( Figure 9 C).…”

“…twice per week. From Week 18 until Week 22, one group of mice ( n = 6) was treated with the dual G9a/DNMT1 inhibitor CM272 [ 17 , 18 ] (5 mg/kg, i.p.) daily, while control mice ( n = 6) received the same volume of PBS.…”

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

“…Moreover, CM-272 counteracts the pro-fibrogenic metabolic reprogramming of HSC and inhibits CCl 4 -induced fibrogenesis in vivo [ 136 ]. The efficacy of CM-272 has also been recently demonstrated in cholangiocarcinoma, a type of hepatobiliary tumor for which no effective systemic therapies exist [ 137 ].…”