Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy.

Magali Humbert, Kristina Seiler, Severin Mosimann, Vreni Rentsch, Katyayani Sharma, Amit V Pandey, Sharon L McKenna, Mario P Tschan

Journal: Cell death and differentiation 2022;28(8):2465-2481

PMID: 33742137

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Abstract

Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis and is often highly expressed in cancer cells. We found that FASN mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34 hematopoietic progenitors. Accordingly, FASN levels decreased during all-trans retinoic acid (ATRA)-mediated granulocytic differentiation of acute promyelocytic leukemia (APL) cells, partially via autophagic degradation. Furthermore, our data suggest that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG) accelerated the differentiation of APL cell lines and significantly re-sensitized ATRA refractory non-APL AML cells. FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis. Together, our data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells.

Address: Institute of Pathology, Division of Experimental Pathology, University of Bern, Bern, Switzerland. [email protected].; TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action, Bern, Switzerland. [email protected].; Institute of Pathology, Division of Experimental Pathology, University of Bern, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.; Institute of Pathology, Division of Experimental Pathology, University of Bern, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.; Pediatric Endocrinology, Diabetology, and Metabolism, University Children's Hospital, Bern, Switzerland.; Department of Biomedical Research, University of Bern, Bern, Switzerland.; Pediatric Endocrinology, Diabetology, and Metabolism, University Children's Hospital, Bern, Switzerland.; Department of Biomedical Research, University of Bern, Bern, Switzerland.; TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action, Bern, Switzerland.; Cancer Research, UCC, Western Gateway Building, University College Cork, Cork, Ireland.; Institute of Pathology, Division of Experimental Pathology, University of Bern, Bern, Switzerland.; TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action, Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

DOI: 10.1038/s41418-021-00768-1