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Article: Adaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species

TitleAdaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species
Authors
Issue Date2021
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2021, v. 74 n. 2, p. 776-796 How to Cite?
AbstractBackground and aims: HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) are excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. Approach and Results: We found that ME1, but not ME3, was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1/nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by superenhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to sorafenib. Therapeutically, simultaneous blockade of NRF2 and a superenhancer complex completely impeded HCC growth. We show that superenhancers allow cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating ME1. Conclusions: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defense against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.
Persistent Identifierhttp://hdl.handle.net/10722/304800
ISSN
2023 Impact Factor: 12.9
2023 SCImago Journal Rankings: 5.011
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLee, D-
dc.contributor.authorZhang, MS-
dc.contributor.authorTsang, FHC-
dc.contributor.authorBao, MHR-
dc.contributor.authorXu, IMJ-
dc.contributor.authorLai, RKH-
dc.contributor.authorChiu, DKC-
dc.contributor.authorTse, APW-
dc.contributor.authorLaw, CT-
dc.contributor.authorChan, CYK-
dc.contributor.authorYuen, VWH-
dc.contributor.authorChui, NNQ-
dc.contributor.authorNg, IOL-
dc.contributor.authorWong, CM-
dc.contributor.authorWong, CCL-
dc.date.accessioned2021-10-05T02:35:22Z-
dc.date.available2021-10-05T02:35:22Z-
dc.date.issued2021-
dc.identifier.citationHepatology, 2021, v. 74 n. 2, p. 776-796-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/304800-
dc.description.abstractBackground and aims: HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) are excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. Approach and Results: We found that ME1, but not ME3, was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1/nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by superenhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to sorafenib. Therapeutically, simultaneous blockade of NRF2 and a superenhancer complex completely impeded HCC growth. We show that superenhancers allow cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating ME1. Conclusions: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defense against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsSubmitted (preprint) Version This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Accepted (peer-reviewed) Version This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.titleAdaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species-
dc.typeArticle-
dc.identifier.emailLee, D: leederek@hku.hk-
dc.identifier.emailZhang, MS: mistyzs@hku.hk-
dc.identifier.emailBao, MHR: macus@connect.hku.hk-
dc.identifier.emailTse, APW: akipwtse@hku.hk-
dc.identifier.emailLaw, CT: ctlawaa@connect.hku.hk-
dc.identifier.emailChan, CYK: ykchanaa@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailWong, CM: jcmwong@hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityWong, CM=rp00231-
dc.identifier.authorityWong, CCL=rp01602-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.31761-
dc.identifier.pmid33619771-
dc.identifier.scopuseid_2-s2.0-85113386466-
dc.identifier.hkuros325828-
dc.identifier.volume74-
dc.identifier.issue2-
dc.identifier.spage776-
dc.identifier.epage796-
dc.identifier.isiWOS:000688494200017-
dc.publisher.placeUnited States-

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