The Role of CENPK Splice Variant in Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Oct 15

PMID 39404386

Authors

Minhong Huang

Sisi Qin

Huanyao Gao

Wootae Kim

Fang Xie

Ping Yin

August John

Richard M Weinshilboum

Liewei Wang

Affiliations

Soon will be listed here.

Abstract

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK-delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK-delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK-delta8 rather than wild-type CENPK, underscoring the role of CENPK-delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine.

Citing Articles

Construction of regulatory T cells specific genes predictive models of prostate cancer patients based on machine learning: a computational analysis and in vitro experiments.

Zhou Z, Liang C Discov Oncol. 2025; 16(1):178.

PMID: 39948230 PMC: 11825432. DOI: 10.1007/s12672-025-01862-3.

References

Wu T, Wang W, Wang Y, Yao M, Du L, Zhang X . Comprehensive analysis of alternative splicing profiling reveals novel events associated with prognosis and the infiltration of immune cells in prostate cancer. Transl Androl Urol. 2021; 10(7):3056-3068. PMC: 8350246. DOI: 10.21037/tau-21-585. View

Mao S, Qian Y, Wei W, Lin X, Ling Q, Ye W . FLOT1 knockdown inhibits growth of AML cells through triggering apoptosis and pyroptosis. Ann Hematol. 2023; 102(3):583-595. DOI: 10.1007/s00277-023-05103-x. View

Jang D, Kwon H, Choi M, Lee J, Pak Y . Sumoylation of Flotillin-1 promotes EMT in metastatic prostate cancer by suppressing Snail degradation. Oncogene. 2019; 38(17):3248-3260. PMC: 6756018. DOI: 10.1038/s41388-018-0641-1. View

Melnyk J, Steri V, Nguyen H, Hwang Y, Gordan J, Hann B . Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1. Oncogene. 2022; 41(11):1536-1549. PMC: 8913362. DOI: 10.1038/s41388-022-02179-z. View

He S, Bhatt R, Brown C, Brown E, Buhr D, Chantranuvatana K . High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat Biotechnol. 2022; 40(12):1794-1806. DOI: 10.1038/s41587-022-01483-z. View

Sotillo E, Barrett D, Black K, Bagashev A, Oldridge D, Wu G . Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015; 5(12):1282-95. PMC: 4670800. DOI: 10.1158/2159-8290.CD-15-1020. View

Robinson D, Van Allen E, Wu Y, Schultz N, Lonigro R, Mosquera J . Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161(5):1215-1228. PMC: 4484602. DOI: 10.1016/j.cell.2015.05.001. View

Olender J, Lee N . Role of Alternative Splicing in Prostate Cancer Aggressiveness and Drug Resistance in African Americans. Adv Exp Med Biol. 2019; 1164:119-139. PMC: 6777849. DOI: 10.1007/978-3-030-22254-3_10. View

Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y . Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov. 2017; 7(7):736-749. PMC: 5501744. DOI: 10.1158/2159-8290.CD-16-1174. View

10.

Chaput G, Sumar N . Endocrine therapies for breast and prostate cancers: Essentials for primary care. Can Fam Physician. 2022; 68(4):271-276. PMC: 9007137. DOI: 10.46747/cfp.6804271. View

11.

Zhao S, Liao J, Zhang S, Shen M, Li X, Zhou L . The positive relationship between androgen receptor splice variant-7 expression and the risk of castration-resistant prostate cancer: A cumulative analysis. Front Oncol. 2023; 13:1053111. PMC: 9972874. DOI: 10.3389/fonc.2023.1053111. View

12.

Wang Y, Bernhardy A, Cruz C, Krais J, Nacson J, Nicolas E . The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res. 2016; 76(9):2778-90. PMC: 4874568. DOI: 10.1158/0008-5472.CAN-16-0186. View

13.

Dehm S, Hillman D, Sicotte H, Tan W, Gormley M, Bhargava V . A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone. Ann Oncol. 2017; 29(2):352-360. PMC: 6304474. DOI: 10.1093/annonc/mdx689. View

14.

Rawla P . Epidemiology of Prostate Cancer. World J Oncol. 2019; 10(2):63-89. PMC: 6497009. DOI: 10.14740/wjon1191. View

15.

Li C, Yu S, Nakamura F, Pentikainen O, Singh N, Yin S . Pro-prion binds filamin A, facilitating its interaction with integrin beta1, and contributes to melanomagenesis. J Biol Chem. 2010; 285(39):30328-39. PMC: 2943319. DOI: 10.1074/jbc.M110.147413. View

16.

Sramkoski R, Pretlow 2nd T, Giaconia J, Pretlow T, Schwartz S, Sy M . A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999; 35(7):403-9. DOI: 10.1007/s11626-999-0115-4. View

17.

Mou Z, Spencer J, McGrath J, Harries L . Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer. Hum Genomics. 2023; 17(1):97. PMC: 10623736. DOI: 10.1186/s40246-023-00545-w. View

18.

Giatromanolaki A, Fasoulaki V, Kalamida D, Mitrakas A, Kakouratos C, Lialiaris T . CYP17A1 and Androgen-Receptor Expression in Prostate Carcinoma Tissues and Cancer Cell Lines. Curr Urol. 2020; 13(3):157-165. PMC: 6944932. DOI: 10.1159/000499276. View

19.

Wang B, Ceniccola K, Hwang S, Andrawis R, Horvath A, Freedman J . Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. Nat Commun. 2017; 8:15921. PMC: 5497057. DOI: 10.1038/ncomms15921. View

20.

Zhao T, Mu X, You Q . Succinate: An initiator in tumorigenesis and progression. Oncotarget. 2017; 8(32):53819-53828. PMC: 5581152. DOI: 10.18632/oncotarget.17734. View