SETDB1 interactions with PELP1 contributes to breast cancer endocrine therapy resistance

被引：23

作者：

Liu, Zexuan ^{[1
,2
]}

Liu, Junhao ^{[1
,2
]}

Ebrahimi, Behnam ^{[1
]}

Pratap, Uday P. ^{[1
]}

He, Yi ^{[1
,3
]}

Altwegg, Kristin A. ^{[1
,6
]}

Tang, Weiwei ^{[1
,4
]}

Li, Xiaonan ^{[1
]}

Lai, Zhao ^{[5
]}

Chen, Yidong ^{[5
,8
]}

Shen, Liangfang ^{[2
]}

Sareddy, Gangadhara R. ^{[1
,6
]}

Viswanadhapalli, Suryavathi ^{[1
,6
]}

Tekmal, Rajeshwar R. ^{[1
,6
]}

Rao, Manjeet K. ^{[5
,6
]}

Vadlamudi, Ratna K. ^{[1
,6
,7
]}

机构：

[1] Univ Texas Hlth San Antonio, Dept Obstet & Gynecol, Div Reprod Res, 7703 Floyd Curl Dr,Mail Code 7836, San Antonio, TX 78229 USA

[2] Cent South Univ, Xiangya Hosp, Dept Oncol, Changsha 410008, Hunan, Peoples R China

[3] Cent South Univ, Xiangya Hosp, Dept Neurosurg, Changsha 410008, Hunan, Peoples R China

[4] Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Dept Obstet & Gynecol, Nanjing 210028, Peoples R China

[5] Univ Texas Hlth San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA

[6] Univ Texas Hlth San Antonio, Mays Canc Ctr, San Antonio, TX 78229 USA

[7] South Texas Vet Hlth Care Syst, Audie Murphy Div, San Antonio, TX 78229 USA

[8] Univ Texas Hlth San Antonio, Dept Populat Hlth Sci, San Antonio, TX 78229 USA

来源：

BREAST CANCER RESEARCH | 2022年 / 24卷 / 01期

关键词：

SETDB1; Akt; PELP1; Breast cancer; Therapy resistance; METHYLTRANSFERASE SETDB1; MOLECULAR-CLONING; GENE-EXPRESSION; MECHANISMS;

D O I：

10.1186/s13058-022-01520-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Methyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance. Methods We utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER+)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance. RNA-seq of parental and SETDB1 knock down ER+ BC cells was used to identify unique pathways. SETDB1 interaction with PELP1 was identified by yeast-two hybrid screen and confirmed by immunoprecipitation and GST-pull down assays. Mechanistic studies were conducted using Western blotting, reporter gene assays, RT-qPCR, and in vitro methylation assays. Xenograft assays were used to establish the role of PELP1 in SETDB1 mediated BC progression. Results RNA-seq analyses showed that SETDB1 regulates expression of a subset of estrogen receptor (ER) and Akt target genes that contribute to endocrine therapy resistance. Importantly, using yeast-two hybrid screen, we identified ER coregulator PELP1 as a novel interacting protein of SETDB1. Biochemical analyses confirmed SETDB1 and PELP1 interactions in multiple BC cells. Mechanistic studies confirmed that PELP1 is necessary for SETDB1 mediated Akt methylation and phosphorylation. Further, SETDB1 overexpression promotes tamoxifen resistance in BC cells, and PELP1 knockdown abolished these effects. Using xenograft model, we provided genetic evidence that PELP1 is essential for SETDB1 mediated BC progression in vivo. Analyses of TCGA datasets revealed SETDB1 expression is positively correlated with PELP1 expression in ER+ BC patients. Conclusions This study suggests that the PELP1/SETDB1 axis play an important role in aberrant Akt activation and serves as a novel target for treating endocrine therapy resistance in breast cancer.

引用

页数：18

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[1] Differential expression analysis for sequence count data [J].