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  • DECEMBER 2018�CANCER DISCOVERY | 1503

    RESEARCH WATCH

    Major finding: Increased fiber fermen- tation amidst microbial dysbiosis may promote tumorigenesis.

    Concept: Enriching foods with refined fermentable fiber induced cholestasis, hepatic inflammation, and tumorigenesis.

    Impact: Consuming foods enriched with fermentable fiber may increase the risk of hepatocellular carcinoma.

    Microbiome

    DYSREGULATED FERMENTATION OF SOLUBLE FIBER MAY INDUCE LIVER CANCER

    The gut microbiota benefi ts the host in part via metabolism of dietary fi ber into valuable nutrients. Insoluble fi ber resists fermentation, but soluble fi ber (such as inulin) is fermented into short-chain fatty acids (SCFA), which have a benefi cial meta- bolic effect. Disruption of the gut microbiota can lead to chronic infl ammation, and mice lacking toll-like receptor 5 (TLR5) are at increased risk for developing microbiota-dependent colitis and infl amma- tion-associated metabolic syndrome. Singh, Yeoh, Chassaing, and colleagues aimed to determine if soluble fi ber might ameliorate the microbial dysbiosis and metabolic syndrome associated with TLR5 defi ciency. Unexpectedly, enrich- ing the diet of the mice with inulin induced hepatocellular carcinoma (HCC) in these innate immune-defi cient mice despite improving glycemic control and reducing adiposity. The inulin diet–induced HCC was associated with hepatic infl ammation and was not specifi c to TLR5 defi ciency, but was triggered in other innate immune-dysregulated mice (including TLR4- and lipcalin-2–defi cient mice). Other solu- ble fi bers (such as pectin and fructooligosaccharides) had a

    similar HCC-promoting effect, but nonferment- able or insoluble fi ber did not promote HCC. HCC development in TLR5-defi cient mice was associ- ated with alterations in gut microbiota (dysbiosis), with an increase in fi ber-fermenting species. The susceptibility of TLR5-defi cient mice to inulin- induced HCC was dependent on dysbiotic micro- biota. Microbial transfer from TLR5-defi cient mice

    rendered wild-type mice susceptible to HCC, whereas micro- bial ablation with broad-spectrum antibiotics prevented HCC development. Inulin-induced tumorigenesis was initiated by early-onset cholestasis that resulted in hepatocyte apoptosis, neutrophil infi ltration, and liver infl ammation. Tumorigen- esis could be blocked by inhibition of fermentation, which resulted in reduced intestinal SCFA. Collectively, these fi nd- ings suggest that enriching processed foods with fermentable fi ber may increase the risk of HCC. ■

    Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R, et al. Dysregulated microbial fermentation of soluble fi ber induces cholestatic liver cancer. Cell 2018;175:679–94.e22.

    Major finding: Cellular mechanotransduction regulates the interaction between ARID1A in the SWI/SNF complex and YAP/TAZ.

    Concept: Under high mechanical stress ARID1A binds to F-actin, reducing its interaction with TAP/TAZ.

    Impact: Full activation of YAP/TAZ may require nuclear accumulation of YAP/ TAZ and inhibition of ARID1A-SWI/SNF.

    Epigenetics

    THE SWI/SNF COMPLEX BINDS TO AND INHIBITS YAP/TAZ ARID1A and other components of the SWI/SNF chro-

    matin remodeling complex are frequently inactivated by genetic alterations in cancer. However, the mechanism by which the SWI/SNF complex suppresses tumorigenesis remains poorly understood. Chang and colleagues found that ARID1A binds to and inhibits the oncogenic tran- scriptional coactivators YAP and TAZ, resulting in reduced expression YAP/TAZ target genes. Inhibiting YAP/TAZ promoted proliferation and liver tumorigenesis in Arid1a- defi cient cells. SWI/SNF has been previously shown to asso- ciate with F-actin, and mechanical cell stress increased the association between nuclear F-actin and ARID1A-SWI/SNF, thereby reducing the association between ARID1A and YAP/ TAZ. YAP/TAZ binds to the DNA-binding platform TEAD to drive transcription, and ARID1A competed with TEAD for binding to YAP/TAZ. Thus, under high mechanical stress F-actin blocked YAP/TAZ from binding to ARID1A, promoting increased association between YAP/TAZ and

    TEAD. In contrast, conditions of low mechanical stress favored the interaction between ARID1A and YAP/TAZ. Consistent with these fi ndings, YAP-expressing neurons formed neurospheres more effi ciently on stiff extracellular matrix (ECM) than on soft ECM, and depletion of Arid1a rescued the ability to form neurospheres on stiff ECM by enhancing the YAP/TAZ–TEAD interaction independent of mechanostress. Taken together, these fi ndings suggest that full activation of YAP/TAZ requires nuclear accumulation of YAP/TAZ in addition to suppression of ARID1A–SWI/ SNF, which can occur via genetic alteration or mechanical stress. Further, these data suggest that the loss of ARID1 in tumor cells may increase the sensitivity to mechanotrans- duction to promote tumorigenesis. ■

    Chang L, Azzolin L, Di Biagio D, Zanconato F, Battilana G, Xic- cato RL, et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 2018;563:265–9. 

    Research. on October 20, 2020. © 2018 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

    Published OnlineFirst October 26, 2018; DOI: 10.1158/2159-8290.CD-RW2018-184

    http://cancerdiscovery.aacrjournals.org/

  • 2018;8:1503. Published OnlineFirst October 26, 2018.Cancer Discov Cancer Dysregulated Fermentation of Soluble Fiber May Induce Liver

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    Published OnlineFirst October 26, 2018; DOI: 10.1158/2159-8290.CD-RW2018-184

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