Super enhancer-associated master transcription factor SOX4 suppresses anti-tumor Immunlty In NAFLD-associated hepatocellular carclinoma
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AbstractHepatocellular carcinoma (HCC) has become a prominent global health threat due to its occurrence and lethality. Increasing prevalence of non-alcoholic fatty liver disease (NAFLD) have been found culpable for HCC initiation, via disruption of the liver microenvironment. Super enhancers (SEs) and master transcription factors (TFs) translate microenvironmental changes into chromatin remodelling and activation, which subsequently disrupt the transcriptome profile and initiate oncogenesis. This project aims at profiling the SE status and unveiling the master regulators involved in diet-induced HCC progression. Nanoscale chromatin immunoprecipitation sequencing (nano ChIP-seq) against histone mark H3K27ac in 10 pairs of primary human NAFLD-HCC tumors and adjacent non-tumor tissues revealed potential tissue-specific SEs (averaged 541 and 512 per HCC tumor and non-tumor tissues, respectively). Global mRNA profile was detected by RNA sequencing (RNA-seq) to support the enhancer-target gene transcription axes in the enriched metabolic and immune response pathways. A non-alcoholic steatohepatitis-induced HCC (NASH-HCC) mouse model was established by subcutaneous injection of a diabetogenic agent streptozotocin (STZ) (200 g) two days after birth followed by a 19-week high-fat high-carbohydrate (HFHC) diet from the age of 4 weeks. Another carcinogen diethylnitrosamine-induced HCC (DEN-HCC) mouse model was established by intraperitoneal injection of DEN (25 mg/kg) followed by a 22-week HFHC diet from the age of 6 weeks. Tumor-enabling SEs were profiled in primary human NAFLD-HCC tissues and a network of master TFs were identified using integrated bioinformatic analysis. Intriguingly, tumor-enabling SEs target critical genes involved in PDGFB signalling and NAFLD pathogenesis, which are significantly correlated with high master TF SOX4 expression. Notable overexpression of Sox4 and Pdgfb was also observed in liver tumors in two HCC mouse models, significantly correlating with the CD11b+ CD11c+ IL10+ IDO+ tolerogenic dendritic cell population. Integrated analysis of ChIP-seq and RNA-seq in primary human tissues revealed a super enhancer-associated master regulatory network in NAFLD-HCC development. Our findings suggest that epigenetic regulation of the SOX4 and PDGFB may contribute to an immunosuppressive liver tumor environment, providing insights for novel therapeutic strategy against this rapidly-increasing dreadful disease.
This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309.
All Author(s) ListKa Wing CHEUNG, Feng WU, Wenshu TANG, Weiqin YANG, Jingying ZHOU, Patrick TAN, Yuk Lap Kevin YIP, Ka Fai TO, Sze Lok Alfred CHENG
Name of ConferenceAmerican Association for Cancer Research Annual Meeting 2019
Start Date of Conference29/03/2019
End Date of Conference03/04/2019
Place of ConferenceAtlanta
Country/Region of ConferenceUnited States of America
Proceedings TitleProceedings of the American Association for Cancer Research
Year2019
Month3
Volume Number60
Pages1341 - 1341
LanguagesEnglish-United States

Last updated on 2019-07-05 at 17:35