Distinct Regulation of ASCL1 by the Cell Cycle and Chemotherapy in Small Cell Lung Cancer

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2024 Mar 21

PMID 38512021

Authors

Yuning Liu

Qingzhe Wu

Bin Jiang

Tingting Hou

Chuanqiang Wu

Ming Wu

Hai Song

Affiliations

Soon will be listed here.

Abstract

Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNEC), which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model, and is regulated by the cell cycle. Mechanistically, CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multisite phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle-regulated protein and provides a theoretical basis for applying cell-cycle-related antitumor drugs in SCLC treatment. Implications:Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating patients with SCLC with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.

References

Sen T, Tong P, Stewart C, Cristea S, Valliani A, Shames D . CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res. 2017; 77(14):3870-3884. PMC: 5563854. DOI: 10.1158/0008-5472.CAN-16-3409. View

Sutherland K, Proost N, Brouns I, Adriaensen D, Song J, Berns A . Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell. 2011; 19(6):754-64. DOI: 10.1016/j.ccr.2011.04.019. View

Rheinbay E, Suva M, Gillespie S, Wakimoto H, Patel A, Shahid M . An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep. 2013; 3(5):1567-79. PMC: 3774301. DOI: 10.1016/j.celrep.2013.04.021. View

Byers L, Rudin C . Small cell lung cancer: where do we go from here?. Cancer. 2014; 121(5):664-72. PMC: 5497465. DOI: 10.1002/cncr.29098. View

Harris L, Rigo P, Stiehl T, Gaber Z, Austin S, Masdeu M . Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population. Cell Stem Cell. 2021; 28(5):863-876.e6. PMC: 8110946. DOI: 10.1016/j.stem.2021.01.003. View

George J, Lim J, Jang S, Cun Y, Ozretic L, Kong G . Comprehensive genomic profiles of small cell lung cancer. Nature. 2015; 524(7563):47-53. PMC: 4861069. DOI: 10.1038/nature14664. View

Ali F, Cheng K, Kirwan P, Metcalfe S, Livesey F, Barker R . The phosphorylation status of Ascl1 is a key determinant of neuronal differentiation and maturation in vivo and in vitro. Development. 2014; 141(11):2216-24. DOI: 10.1242/dev.106377. View

Augustyn A, Borromeo M, Wang T, Fujimoto J, Shao C, Dospoy P . ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc Natl Acad Sci U S A. 2014; 111(41):14788-93. PMC: 4205603. DOI: 10.1073/pnas.1410419111. View

Noronha V, Sekhar A, Patil V, Menon N, Joshi A, Kapoor A . Systemic therapy for limited stage small cell lung carcinoma. J Thorac Dis. 2020; 12(10):6275-6290. PMC: 7656383. DOI: 10.21037/jtd-2019-sclc-11. View

10.

Wu Q, Guo J, Liu Y, Zheng Q, Li X, Wu C . YAP drives fate conversion and chemoresistance of small cell lung cancer. Sci Adv. 2021; 7(40):eabg1850. PMC: 10938532. DOI: 10.1126/sciadv.abg1850. View

11.

Bernassola F, Karin M, Ciechanover A, Melino G . The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell. 2008; 14(1):10-21. DOI: 10.1016/j.ccr.2008.06.001. View

12.

Vinals F, Reiriz J, Ambrosio S, Bartrons R, Rosa J, Ventura F . BMP-2 decreases Mash1 stability by increasing Id1 expression. EMBO J. 2004; 23(17):3527-37. PMC: 516632. DOI: 10.1038/sj.emboj.7600360. View

13.

Errico A, Deshmukh K, Tanaka Y, Pozniakovsky A, Hunt T . Identification of substrates for cyclin dependent kinases. Adv Enzyme Regul. 2010; 50(1):375-99. DOI: 10.1016/j.advenzreg.2009.12.001. View

14.

Somasundaram K, Reddy S, Vinnakota K, Britto R, Subbarayan M, Nambiar S . Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene. 2005; 24(47):7073-83. DOI: 10.1038/sj.onc.1208865. View

15.

Byers L, Wang J, Nilsson M, Fujimoto J, Saintigny P, Yordy J . Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012; 2(9):798-811. PMC: 3567922. DOI: 10.1158/2159-8290.CD-12-0112. View

16.

Blomfield I, Rocamonde B, Masdeu M, Mulugeta E, Vaga S, van den Berg D . Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells. Elife. 2019; 8. PMC: 6805120. DOI: 10.7554/eLife.48561. View

17.

Koduri V, Duplaquet L, Lampson B, Wang A, Sabet A, Ishoey M . Targeting oncoproteins with a positive selection assay for protein degraders. Sci Adv. 2021; 7(6). PMC: 7864573. DOI: 10.1126/sciadv.abd6263. View

18.

Abdo Hassan W, Takebayashi S, Abdalla M, Fujino K, Kudoh S, Motooka Y . Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma. Lab Invest. 2017; 97(8):913-921. DOI: 10.1038/labinvest.2017.36. View

19.

Borromeo M, Savage T, Kollipara R, He M, Augustyn A, Osborne J . ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell Rep. 2016; 16(5):1259-1272. PMC: 4972690. DOI: 10.1016/j.celrep.2016.06.081. View

20.

Borges M, Linnoila R, van de Velde H, Chen H, Nelkin B, MABRY M . An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature. 1997; 386(6627):852-5. DOI: 10.1038/386852a0. View