Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer

Loo, Ser Yue; Toh, Li Ping; Xie, William Haowei; Pathak, Elina; Tan, Wilson Wei Sheng; Ma, Siming; Lee, May Yin; Shatishwaran, S.; Yeo, Joanna Zhen Zhen; Yuan, Ju; Ho, Yin Ying; Peh, Esther Kai Lay; Muniandy, Magendran; Torta, Federico; Chan, Jack Junjie; Tan, Tira J.; Sim, Yirong; Tan, Veronique Kiak‐Mien; Tan, Benita Kiat‐Tee; Madhukumar, Preetha; Yong, Wei Sean; Ong, Kong Wee; Wong, Chow Yin; Tan, Puay Hoon; Yap, Yoon Sim; Deng, Lih‐Wen; Dent, Rebecca; Foo, Roger; Wenk, Markus R.; Lee, Soo‐Chin; Ho, Ying Swan; Lim, Elaine; Tam, Wai Leong

doi:10.1126/sciadv.abh2443

Cited by 57 publications

(41 citation statements)

References 79 publications

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“…Increasing reports demonstrated that FAO contributed to chemoresistance in gastric [ 28 ], breast [ 29 ], ovarian [ 30 ], and hepatocellular carcinomas [ 31 ]. Pharmacological inhibition of FAO sensitized leukemia cells to apoptosis [ 32 ], and synergetic of FAO inhibitors with Ara-C eradicated bone marrow resident chemoresistance AML cells [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Zhang

Shen

Wei

et al. 2022

IJMS

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Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Zhang

Shen

Wei

et al. 2022

IJMS

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“…Here, we performed a meta-analysis of oncovirus-positive samples in interconnected axes of cellular plasticity: EMT, metabolic reprogramming, and immune checkpoint expression (Dongre et al 2021; Jia et al 2021; Loo et al 2021; Lv et al 2021; Sahoo et al 2021). While crosstalk among these axes has been investigated in multiple cancers, their interconnection specifically in oncovirus-positive scenarios remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Partial EMT and associated changes in cellular plasticity in oncovirus-positive samples

Sehgal¹,

Ray²,

Vaz

et al. 2022

Preprint

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Oncoviruses exploit diverse host mechanisms to survive and proliferate. These adaptive strategies overlap with mechanisms employed by malignant cells during their adaptation to dynamic micro-environments and for evasion of immune attack. While the role of individual oncoviruses in mediating cancer progression has been extensively characterized, little is known about the common gene regulatory features of oncovirus-induced cancers. Here, we focus on defining the interplay between several cancer hallmarks, including Epithelial- Mesenchymal Transition (EMT), metabolic alterations, and immune evasion across major oncoviruses by examining publicly-available transcriptomics data sets containing both oncovirus-positive and oncovirus-negative samples. We observe that oncovirus-positive samples display varying degrees of EMT and metabolic reprogramming. While the progression of EMT generally associated with an enriched glycolytic metabolic program and suppressed fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), partial EMT correlated well with glycolysis. Furthermore, oncovirus-positive samples had higher activity and/or expression levels of immune checkpoint molecules, such as PD-L1, which was associated with a partial EMT program. These analyses thus decode common pathways in oncovirus-positive samples that may be used in pinpointing new therapeutic vulnerabilities for oncovirus-associated cancer cell plasticity.

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“…Acetyl-CoA levels have been previously linked to protein acetylation of Smad induced by leptin signaling 63 and histone acetylation 64-66 with subsequent breast cancer metastasis 63,64 . We add to this current knowledge by defining p65 as an acetylation target modulated by palmitate-derived acetyl-CoA.…”

Section: Discussionmentioning

confidence: 99%

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation

Altea-Manzano

Doglioni

Cuadros

et al. 2022

Preprint

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Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-kB subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-kB signaling.

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Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer

Abstract: Fatty acid oxidation is a metabolic gateway that regulates cellular plasticity and supports metastasis in breast cancer.

Cited by 57 publications

References 79 publications

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation

Partial EMT and associated changes in cellular plasticity in oncovirus-positive samples

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation

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