SUMOylation inhibition enhances dexamethasone sensitivity in multiple myeloma

Journal of Experimental & Clinical Cancer Research

Alex Pozhitkov¹  Grace Aldana-Masangkay²  Yuan Chen³  Flavia Pichiorri⁴  Wei Liu⁵  Li Du⁶  Steven T. Rosen⁷ 

[1] Department of Informatics, City of Hope National Medical Center, Duarte, CA, USA;Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA;Present address: Fulgent Genetics, City, 91780, Temple City, CA, USA;Department of Surgery and Moores Cancer Center, UC San Diego Health, San Diego, CA, USA;Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA;Department of Hematology and Stem Cell Transplant, Beckman Research Institute of City of Hope, Duarte, CA, USA;Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA;Department of Hematology, Xiangya Hospital, Central South University, Changsha, China;Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA;Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA;Department of Hematology and Stem Cell Transplant, Beckman Research Institute of City of Hope, Duarte, CA, USA;Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA;Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA;Department of Hematology and Stem Cell Transplant, Beckman Research Institute of City of Hope, Duarte, CA, USA;City of Hope Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA, USA;

关键词: Multiple myeloma;    SUMOylation;    Dexamethasone;    microRNA;   

DOI  :  10.1186/s13046-021-02226-9

来源: Springer

【 摘 要 】

BackgroundMultiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM.MethodsUsing MM cell lines and primary MM samples from relapsing MM patients, we evaluated the effects of knockdown of SUMO E1 (SAE2) or using TAK-981, a novel and specific SUMO E1 inhibitor, on Dex sensitivity. Xenograft mouse models were generated to determine the in vivo anti-MM effects of TAK-981 as a single agent and in combination with Dex. miRNA-seq, RNA-seq and GSEA analysis were utilized for evaluating key factors mediating Dex resistance. Chromatin immunoprecipitation (ChIP) assay was performed to determine the binding occupancy of c-Myc on promoter region of miRs.ResultsWe observed a significant negative correlation between SUMO E1 (SAE2) expression and Dex sensitivity in primary MM samples. Knockdown of SAE2 or using TAK-981 significantly enhances myeloma sensitivity to Dex in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Dex combination has been validated using primary relapsing MM patient samples and xenograft mouse models. SUMOylation inhibition increased glucocorticoid receptor (GR) expression via downregulation miR-130b. Using RNA and microRNA sequencing, we identified miR-551b and miR-25 as important miRs mediating Dex resistance in MM. Overexpression of miR-551b and miR-25 caused resistance to Dex, however, knockdown of miR-551b and miR-25 significantly enhanced Dex sensitivity in MM. SAE2 knockdown or TAK-981 treatment downregulated the expression of miR-551b and miR-25, leading to induction of miR targets ZFP36, ULK1 and p27, resulting in apoptosis and autophagy. We demonstrated c-Myc as a major transcriptional activator of miR-130b, miR-551b and miR-25 and SUMOylation inhibition downregulates these miRs level by decreasing c-Myc level.ConclusionOur study proves SUMOylation plays a crucial role in Dex resistance in MM and SUMOylation inhibition appears to be an attractive strategy to advance to the clinic for MM patients.

【 授权许可】

CC BY