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SMARCA4 oncogenic potential via IRAK1 enhancer to activate Gankyrin and AKR1B10 in liver cancer

Oncogene volume 40, pages 4652–4662 (2021)Cite this article

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Abstract

SWItch/Sucrose Non-Fermentable (SWI/SNF) is a multiprotein complex essential for the regulation of eukaryotic gene expression. SWI/SNF complex genes are genetically altered in over 20% of human malignancies, but the aberrant regulation of the SWI/SNF subunit genes and subsequent dysfunction caused by abnormal expression of subunit gene in cancer, remain poorly understood. Among the SWI/SNF subunit genes, SMARCA4, SMARCC1, and SMARCA2 were identified to be overexpressed in human hepatocellular carcinoma (HCC). Modulation of SMARCA4, SMARCC1, and SMARCA2 inhibited in vitro tumorigenesis of HCC cells. However, SMARCA4-targeting elicited remarkable inhibition in an in vivo Ras-transgenic mouse HCC model (Ras-Tg), and high expression levels of SMARCA4 significantly associated with poor prognosis in HCC patients. Furthermore, most HCC patients (72–86%) showed SMARCA4 overexpression compared to healthy controls. To identify SMARCA4-specific active enhancers, mapping, and analysis of chromatin state in liver cancer cells were performed. Integrative analysis of SMARCA4-regulated genes and active chromatin enhancers suggested 37 genes that are strongly activated by SMARCA4 in HCC. Through chromatin immunoprecipitation-qPCR and luciferase assays, we demonstrated that SMARCA4 activates Interleukin-1 receptor-associated kinase 1 (IRAK1) expression through IRAK1 active enhancer in HCC. We then showed that transcriptional activation of IRAK1 induces oncoprotein Gankyrin and aldo–keto reductase family 1 member B10 (AKR1B10) in HCC. The regulatory mechanism of the SMARCA4-IRAK1-Gankyrin, AKR1B10 axis was further demonstrated in HCC cells and in vivo Ras-Tg mice. Our results suggest that aberrant overexpression of SMARCA4 causes SWI/SNF to promote IRAK1 enhancer to activate oncoprotein Gankyrin and AKR1B10, thereby contributing to hepatocarcinogenesis.

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Fig. 1: Genetic alteration and aberrant expression of SWI/SNF subunit genes in HCC.
Fig. 2: In vitro tumorigenicity of SMARCA4, SMARCA2, and SMARCC1 in HCC cells.
Fig. 3: Metastatic potential of SMARCA4 and in vivo tumorigenicity of SMARCA4, SMARCA2, and SMARCC1 in mouse HCC model.
Fig. 4: Identification of specific target gene regulated by SMARCA4 in HCC.
Fig. 5: Targeted-inhibition of IRAK1 elicits anti-tumor effect in HCC cells.
Fig. 6: Tumorigenic potential of SMARCA4 via activation of IRAK1 in HCC.
Fig. 7: SMARCA4 regulates IRAK1 to activate Gankyrin and AKR1B10 in HCC in vitro and in vivo.

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Acknowledgements

We acknowledge support from the National Research Foundation (NRF) of Korea (2017R1A2B3002989 and 2021M3E5E7021893).

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Authors and Affiliations

  1. Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Sang Yean Kim, Qingyu Shen, Min Jeong Na, Eunbi Shin, Suji Yu, Won Sang Park & Suk Woo Nam

  2. Functional RNomics Research Center, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Sang Yean Kim, Min Jeong Na, Eunbi Shin, Suji Yu, Won Sang Park & Suk Woo Nam

  3. Department of Biomedicine & Health Sciences, Graduate School of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Sang Yean Kim, Min Jeong Na, Eunbi Shin, Suji Yu & Suk Woo Nam

  4. Department of Microbiology, Dankook University, Cheonan, 31116, Republic of Korea

    Keunhong Son & Keunsoo Kang

  5. NEORNAT Inc, Rm# 305 Medical School Building, 222 Banpo-daero, Seocho-gu, 06591, Seoul, Republic of Korea

    Hyung Seok Kim, Hee Doo Yang & Suk Woo Nam

  6. Department of Biochemistry, Research Institute of Medical Science, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea

    Jueng Soo You

  7. Department of Agricultural Biotechnology, Seoul National University, Seoul, 08826, Republic of Korea

    Kyung-Rok Yu

  8. Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Seung Min Jeong & Eun Kyung Lee

  9. Department of Kidney System, College of Oriental Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea

    Young Min Ahn

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  1. Sang Yean Kim
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Contributions

Study conception and design: SYK, QS and SWN Acquisition of data: SYK, QS Analysis and interpretation of data: SYK, QS, HSK, HDY, MJN, ES, SY, KK, JSY, KY, SMJ, EKL, YMA, and WSP and Drafting of the paper: SWN. Critical revision of the paper: all authors. Technical and material support: SWN. Study supervision: SWN.

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Correspondence to Suk Woo Nam.

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SWN is the chief execute officer of NEORNAT, Inc. HSK and HDY are employee of NEORNAT, Inc. The other authors declare no conflict of interest relating to this work.

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Kim, S.Y., Shen, Q., Son, K. et al. SMARCA4 oncogenic potential via IRAK1 enhancer to activate Gankyrin and AKR1B10 in liver cancer. Oncogene 40, 4652–4662 (2021). https://doi.org/10.1038/s41388-021-01875-6

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