LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells

Juan Carlos Hernandez; Chia-Lin Chen; Tatsuya Machida; Dinesh Babu Uthaya Kumar; Stanley M Tahara; Jared Montana; Linda Sher; Jake Liang; Jae U Jung; Hidekazu Tsukamoto; Keigo Machida

doi:10.1016/j.isci.2023.106254

LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells

iScience. 2023 Feb 22;26(3):106254. doi: 10.1016/j.isci.2023.106254. eCollection 2023 Mar 17.

Authors

Juan Carlos Hernandez^{1

2}, Chia-Lin Chen^{1

3}, Tatsuya Machida¹, Dinesh Babu Uthaya Kumar¹, Stanley M Tahara¹, Jared Montana¹, Linda Sher⁴, Jake Liang⁵, Jae U Jung¹, Hidekazu Tsukamoto^{6

7

8}, Keigo Machida^{1

7}

Affiliations

¹ Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
² MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA.
³ Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan.
⁴ Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA.
⁵ NIDDK, Bethesda, DC, USA.
⁶ Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA.
⁷ Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
⁸ Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Abstract

Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 (caTLR4) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC.

Keywords: Cancer; Cell biology.

Abstract

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