☆ 4.7 Review

Hepatocyte nuclear factor 4 a (HNF4α): A perspective in cancer

BIOMEDICINE & PHARMACOTHERAPY (2023)

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Article Biochemistry & Molecular Biology

KIF14 promotes proliferation, lymphatic metastasis and chemoresistance through G3BP1/YBX1 mediated NF-κB pathway in cholangiocarcinoma

Wangjie Jiang et al.

Summary: Cholangiocarcinoma (CCA) is a highly lethal and fetal cancer derived from the hepatobiliary system. The upregulation of KIF14 in CCA samples is associated with worse overall survival and recurrence-free survival, as well as increased proliferation, migration, invasion, and lymphatic metastasis of CCA cells. Mechanistically, KIF14 binds to the G3BP1/YBX1 complex and enhances their interaction, leading to the activation of the NF-kappa B pathway. Additionally, KIF14 plays a role in chemotherapy resistance and induction of an immunosuppressive microenvironment. In summary, KIF14 could serve as a potential oncogene and a valuable indicator for prognosis and chemotherapy guidance in CCA patients.

ONCOGENE (2023)

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Article Cell Biology

HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer

Qingqing Zhou et al.

Summary: BAP31 is upregulated in gastric cancer tissues and high expression is associated with poor survival of patients. BAP31 knockdown inhibits cell growth, induces G1/S arrest, and promotes cellular ferroptosis by increasing membrane lipid peroxidation. BAP31 directly binds to VDAC1, affecting its oligomerization and polyubiquitination, and is regulated by HNF4A at the promoter. Knockdown of BAP31 sensitizes gastric cancer cells to 5-FU and the ferroptosis inducer erastin.

CELL DEATH & DISEASE (2023)

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Article Oncology

b-Catenin Drives Butyrophilin-like Molecule Loss and gd T-cell Exclusion in Colon Cancer

Toshiyasu Suzuki et al.

Summary: Colon cancer cells evade immune surveillance by suppressing the expression of y8 T cells and Butyrophilin-like (BTNL) molecules. Reexpression of BTNL enhances the survival and activation of y8 T cells, but it does not affect their cancer-killing ability or recruitment to orthotopic tumors. However, inhibition of 13-catenin signaling through genetic deletion of Bcl9/Bcl9L restores the expression of Hnf4a, Hnf4g, and Btnl genes as well as infiltration of y8 T cells into tumors.

CANCER IMMUNOLOGY RESEARCH (2023)

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Article Pharmacology & Pharmacy

The current trend of exosome in epithelial ovarian cancer studies: A bibliometric review

Neda Baghban et al.

Summary: This study aimed to investigate the research output of exosomes in epithelial ovarian cancer (EOC). The findings showed that China had the highest research output, international collaborations, institutions, authors, and financial support. The research also revealed academic interest in exosomes as prognostic biomarkers, cell proliferation and migration, metastasis, epithelial-mesenchymal transition, and the role of exosomes in conferring chemoresistance in EOC.

FRONTIERS IN PHARMACOLOGY (2023)

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Article Multidisciplinary Sciences

Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase

Valeria Besskaya et al.

Summary: This study found that the expression of HNF4A significantly decreased in the ferroptosis of A549 lung adenocarcinoma cells, and this change was blocked by the ferroptosis inhibitor deferoxamine. Knockdown of HNF4A inhibited ferroptosis in A549 cells while overexpression of HNF4A promoted ferroptosis in H23 cells. POR was identified as a key ferroptosis-related gene that serves as a potential target of HNF4A, and its expression was significantly changed in lung adenocarcinoma cells with altered HNF4A expression. HNF4A was shown to enhance POR expression by binding to its promoter, and restoration of POR expression blocked the promoting effect of HNF4A on ferroptosis in lung adenocarcinoma.

PEERJ (2023)

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Review Endocrinology & Metabolism

HNF4 & alpha; isoforms: the fraternal twin master regulators of liver function

Sarah H. H. Radi et al.

Summary: Since the purification and cloning of Hepatocyte Nuclear Factor 4 (HNF4a) more than 30 years ago, we have gained considerable insight into its role in liver function through its target genes and mouse experiments. HNF4a is a key player in lipid and glucose metabolism, and it intersects with diabetes, circadian rhythms, and liver cancer, although further research is needed to fully understand these interactions. While the isoforms expressed from its two promoters are being elucidated, little is known about the alternatively spliced variants in other regions of the protein and their impact on the 1000-plus HNF4a target genes.

FRONTIERS IN ENDOCRINOLOGY (2023)

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Article Biotechnology & Applied Microbiology

Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation

Yueyuan Zheng et al.

Summary: Researchers analyzed whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes, revealing distinct DNA methylation features and partially methylated domains (PMDs) associated with transcription repression, chromatin compartments, and somatic mutation rate. They also found that these features co-occur in other cancers originating from the same cell types.

GENOME BIOLOGY (2023)

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Article Cell & Tissue Engineering

SATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling

Wei Gu et al.

Summary: SATB2 plays a crucial role in maintaining the identity of adult colonic stem cells and epithelial cells in mice and humans.

CELL STEM CELL (2022)

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Article Gastroenterology & Hepatology

A GATA6-centred gene regulatory network involving HNFs and Delta Np63 controls plasticity and immune escape in pancreatic cancer

Bernhard Kloesch et al.

Summary: The loss of GATA6 is identified as a necessary factor for the development of highly aggressive PDAC subtype, along with the concomitant loss of HNF1A and HNF4A. Deletion of Gata6 in mice significantly increases the metastatic rate of tumors, with a propensity for lung metastases.

GUT (2022)

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Article Biochemical Research Methods

High Diversity of Glycosphingolipid Glycans of Colorectal Cancer Cell Lines Reflects the Cellular Differentiation Phenotype

Di Wang et al.

Summary: This study provides an in-depth analysis of glycosphingolipid (GSL) glycans in colorectal cancer (CRC) cell lines. The expression of GSLs varies among different cell line classifications, with undifferentiated cell lines showing high expression of blood group A, B, and H antigens, while colon-like cell lines exhibit prominent expression of (sialyl)-Lewis(A/X) and Lewis(B/Y) antigens. The GSL expression is correlated with relevant glycosyltransferases and transcription factors implicated in colon differentiation.

MOLECULAR & CELLULAR PROTEOMICS (2022)

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Article Biochemistry & Molecular Biology

Aldehyde dehydrogenase 6 family member A1 negatively regulates cell growth and to cisplatin sensitivity in bladder cancer

Qi Guo et al.

Summary: ALDH6A1 is found to have decreased expression in bladder cancer tissues and cell lines. Knocking down ALDH6A1 promotes cell growth, colony formation, and cisplatin resistance, while upregulating ALDH6A1 through HNF4a inhibits cell growth, colony formation, and improves cisplatin sensitivity. ALDH6A1 could potentially serve as a diagnostic marker and treatment target in bladder cancer.

MOLECULAR CARCINOGENESIS (2022)

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Article Genetics & Heredity

HNF1A POU Domain Mutations Found in Japanese Liver Cancer Patients Cause Downregulation of HNF4A Promoter Activity with Possible Disruption in Transcription Networks

Effi Haque et al.

Summary: HNF1A is a master regulator of liver homeostasis and organogenesis. Mutations in the gene can lead to downregulation of HNF1A target genes and potentially promote hepatocellular carcinoma through disruption of transcriptional networks.

GENES (2022)

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Article Biochemistry & Molecular Biology

Chromosomally Unstable Gastric Cancers Overexpressing Claudin-6 Disclose Cross-Talk between HNF1A and HNF4A, and Upregulated Cholesterol Metabolism

Sanyog Dwivedi et al.

Summary: Abnormally increased expression of Claudin-6 in gastric cancer is associated with the chromosomal unstable molecular subtype and worse prognosis. The expression of Claudin-6 is correlated with higher mutations in genes such as TP53, MIEN1, STARD3, PGAP3, and CCNE1.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Oncology

N4BP3 promotes angiogenesis in hepatocellular carcinoma by binding with KAT2B

Hexu Han et al.

Summary: N4BP3 is identified as a novel pro-angiogenic factor in HCC, and its overexpression is positively correlated with tumor microvessel density. N4BP3 regulates STAT3 expression by interacting with KAT2B, thereby affecting the proliferation of microvessels in HCC and the malignant progression of the tumor.

CANCER SCIENCE (2022)

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Letter Gastroenterology & Hepatology

HNF4A Defines Molecular Subtypes and Vulnerability to Transforming Growth Factor β-Pathway Targeted Therapies in Cancers of the Distal Esophagus

Andrew E. Blum et al.

GASTROENTEROLOGY (2022)

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Article Genetics & Heredity

Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

Winston R. Becker et al.

Summary: Single-cell ATAC-seq and RNA-seq profiling were used to study the transformation process from healthy colon to precancerous adenomas to colorectal cancer. Most of the polyp and CRC cells exhibited a stem-like phenotype. The study identified a continuum of epigenetic and transcriptional changes that occur in stem-like cells as they progress from homeostasis to CRC. The results also revealed the presence of T cell exhaustion and specific fibroblast subtypes in advanced polyps and cancerous states. Additionally, DNA methylation changes were found to be negatively correlated with accessibility changes, providing potential regulatory markers for polyp staging.

NATURE GENETICS (2022)

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Review Oncology

The role of YAP1 in liver cancer stem cells: proven and potential mechanisms

Haofeng Wu et al.

Summary: This article reviews the role of YAP1 in liver cancer stem cells and its correlation with tumor initiation and progression.

BIOMARKER RESEARCH (2022)

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Article Pharmacology & Pharmacy

AMPK alpha 2/HNF4A/BORIS/GLUT4 pathway promotes hepatocellular carcinoma cell invasion and metastasis in low glucose microenviroment

Yuan Huang et al.

Summary: This study revealed that activation of the AMPK alpha 2/ HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells. HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.

BIOCHEMICAL PHARMACOLOGY (2022)

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Editorial Material Gastroenterology & Hepatology

Transcription factors as drivers of distinct pancreatic ductal adenocarcinoma (PDAC) programmes: a role for HNF4A

Giuseppe Riccardo Diaferia et al.

GUT (2021)

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Article Biochemistry & Molecular Biology

Immunohistochemical analysis of HNF4A and β-catenin expression to predict low-grade dysplasia in the colitis-neoplastic sequence

Yiping He et al.

Summary: The study found that increased expressions of nuclear P1-/P2-driven HNF4A and cytoplasmic beta-catenin were observed in the colitis-neoplastic sequence, suggesting that both could potentially serve as biomarkers to predict low-grade dysplasia.

ACTA BIOCHIMICA ET BIOPHYSICA SINICA (2021)

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Article Biotechnology & Applied Microbiology

Silencing of long non-coding RNA XIST represses gastric cancer progression through blocking NFκB pathway via inhibiting HNF4A-mediated transcription of EPHA1

Ping Li et al.

Summary: This study identified the functional significance of XIST in gastric cancer (GC) progression by showing that XIST elevated EPHA1 expression by recruiting HNF4A. Silencing of XIST inhibited GC progression in vitro and in vivo, while overexpressed XIST and EPHA1 had a reversed effect on cell proliferation and invasion. The study also demonstrated that XIST increases the enrichment of HNF4A in the promoter region of EPHA1, thus promoting the deterioration of GC.

CANCER GENE THERAPY (2021)

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Article Oncology

The HNF4 alpha-BC200-FMR1-Positive Feedback Loop Promotes Growth and Metastasis in Invasive Mucinous

Xiong Chen et al.

Summary: The study identified a novel HNF4α-BC200-FMR1 positive feedback loop in promoting mRNA stability and metastasis during invasive mucinous lung adenocarcinoma (IMA) progression, providing a targeted therapeutic strategy for IMA.

CANCER RESEARCH (2021)

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Article Oncology

Antisense RNAs Influence Promoter Usage of Their Counterpart Sense Genes in Cancer

Fernando Bellido Molias et al.

Summary: This study identifies ncNATs in hepatocellular carcinoma that regulate isoform expression of associated sense genes through specific promoter mechanisms. These ncNATs demonstrate a context-specific control of alternative isoform expression, highlighting a mechanism of alternative promoter usage in cancer progression.

CANCER RESEARCH (2021)

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Review Biochemistry & Molecular Biology

Hepatocyte nuclear factor 4α and cancer-related cell signaling pathways: a promising insight into cancer treatment

Duo-Duo Lv et al.

Summary: HNF4α, a member of the nuclear receptor superfamily, plays crucial roles in the occurrence, progression, and treatment of cancer. Its abnormal expression is associated with various cellular processes in cancer cells.

EXPERIMENTAL AND MOLECULAR MEDICINE (2021)

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Article Genetics & Heredity

Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer

Taotao Sheng et al.

Summary: The study presents a comprehensive catalog of GC-associated enhancers and shows that combining histone modification and functional assay data improves the prediction of enhancer activity, providing insights into the mechanisms of enhancer heterogeneity.

GENOME MEDICINE (2021)

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Article Biology

Src family kinases inhibit differentiation of intestinal epithelial cells through the Hippo effector YAP1

Sepideh Fallah et al.

Summary: This study reveals the regulatory mechanism of YAP1 in intestinal cell differentiation and demonstrates the impact of SFKs on YAP1 expression and intestinal cell specific gene expression. The results suggest that YAP1 and TAZ are not always interchangeable in regulating cell functions.

BIOLOGY OPEN (2021)

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Article Gastroenterology & Hepatology

Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease-Associated Colorectal Cancer

Kristiina Rajamaki et al.

Summary: By comprehensively characterizing IBD-associated tumorigenesis using multiple high-throughput approaches, distinct mechanisms of WNT pathway dysregulation were identified in IBD-CRC, which skew the tumors towards a mesenchymal subtype. Additionally, epigenetic modifications and noncoding mutations in specific genes were found in IBD-CRC, highlighting further differences compared to sCRC.

GASTROENTEROLOGY (2021)

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A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes

Yueyuan Zheng et al.

Summary: A subset of CpG Island promoter genes are regulated by Polycomb-Repressive Complex 2 (PRC2(+)-CGI), which become DNA hypermethylated and silenced in cancer. The study shows that these upregulated PRC2(+)-CGI genes control important pathways such as Epithelial-Mesenchymal Transition (EMT) and TNF alpha-associated inflammatory response, and have greater cancer-type specificity than other CGI genes. The regulatory plasticity of these genes is highlighted by their complex control mechanisms during normal development.

NATURE COMMUNICATIONS (2021)

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Diagnostic utility of the combined use of HNF4A and GATA3 in distinction between primary and metastatic breast and gastric carcinomas

Diana Z. Saad et al.

Summary: The study evaluated the role of HNF4A and GATA3 in distinguishing breast and gastric carcinomas, finding HNF4A to be expressed in gastric adenocarcinomas but not in breast carcinomas. GATA3 showed high sensitivity and specificity for breast carcinomas.

APMIS (2021)

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Article Cell Biology

LOC100996425 acts as a promoter in prostate cancer by mediating hepatocyte nuclear factor 4A and the AMPK/mTOR pathway

Xiuyan Wang et al.

Summary: This study investigated the impact of LOC100996425 on prostate cancer by targeting HNF4A through the AMPK/mTOR pathway. Results showed that LOC100996425 can enhance the proliferation and migration of PCa cells by down-regulating HNF4A, leading to increased apoptosis.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model

Taihua Yang et al.

Summary: This study demonstrates the therapeutic utility of HNF4A mRNA delivery for liver fibrosis and cirrhosis in mouse models, showing restoration of hepatocyte functions and inhibition of fibrogenesis. The research reveals that HNF4A directly targets PON1, contributing to the attenuation of liver fibrosis through modulation of liver macrophages and hepatic stellate cells.

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Karol Nowicki-Osuch et al.

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SCIENCE (2021)

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Multiomics analysis identifies key genes and pathways related to N6-methyladenosine RNA modification in ovarian cancer

Haoya Xu et al.

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Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Zhen Ni et al.

Summary: The study revealed that P1-HNF4A is a major oncogene in gastric cancer, with its overexpression promoting tumor growth and metastasis. High expression of P1-HNF4A is associated with poor prognosis in GC patients. Additionally, the cytokine-cytokine receptor interaction pathway plays a crucial role in GC progression and may serve as a potential therapeutic target.

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HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer

Chang Xu et al.

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Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015

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LncRNA LINP1 regulates acute myeloid leukemia progression via HNF4α/AMPK/WNT5A signaling pathway

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YAP integrates the regulatory Snail/HNF4α circuitry controlling epithelial/hepatocyte differentiation

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P1 promoter-driven HNF4α isoforms are specifically repressed by β-catenin signaling in colorectal cancer cells

Jean-Philippe Babeu et al.

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CCAAT-enhancer binding protein-α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) regulate expression of the human fructose-1,6-bisphosphatase 1 (FBP1) gene in human hepatocellular carcinoma HepG2 cells

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PLOS ONE (2018)

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Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma

Baharan Fekry et al.

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Yes-Associated Protein/TEA Domain Family Member and Hepatocyte Nuclear Factor 4-Alpha (HNF4α) Repress Reciprocally to Regulate Hepatocarcinogenesis in Rats and Mice

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HEPATOLOGY (2017)

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Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Supriya K. Saha et al.

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CXCR7 correlates with the differentiation of hepatocellular carcinoma and suppresses HNF4α expression through the ERK pathway

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Multiple post-translational modifications in hepatocyte nuclear factor 4α

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Novel P2 promoter-derived HNF4α isoforms with different N-terminus generated by alternate exon insertion

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The Hippo-YAP pathway: new connections between regulation of organ size and cancer

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Differentiation Therapy of Hepatocellular Carcinoma in Mice with Recombinant Adenovirus Carrying Hepatocyte Nuclear Factor-4α Gene

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The expression of hepatocyte nuclear factor-4α, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas

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Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma

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Snail controls differentiation of hepatocytes by repressing HNF4α expression

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Hepatocyte nuclear factor 4α orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2006)

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Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer

T Tanaka et al.

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Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis

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