SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer

Liu, Xi-Yu; Jiang, Wang; Ma, Ding; Ge, Li-Ping; Yang, Yun-Song; Gou, Zong-Chao; Xu, Xiao-En; Shao, Zhi-Ming; Jiang, Yi-Zhou

doi:10.7150/thno.45207



Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

Nanotheranostics

International Journal of Biological Sciences

International Journal of Medical Sciences

Journal of Cancer

Global reach, higher impact

Full Text | PDF

Theranostics 2020; 10(24):10940-10956. doi:10.7150/thno.45207 This issue Cite

Research Paper

SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer

Xi-Yu Liu^1#, Wang Jiang^2#, Ding Ma¹, Li-Ping Ge¹, Yun-Song Yang¹, Zong-Chao Gou¹, Xiao-En Xu¹, Zhi-Ming Shao^1✉, Yi-Zhou Jiang^1✉

1. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
2. University of Chinese Academy of Sciences, Beijing 100049, China.
#These authors contributed equally to this work.

Citation:

Liu XY, Jiang W, Ma D, Ge LP, Yang YS, Gou ZC, Xu XE, Shao ZM, Jiang YZ. SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer. Theranostics 2020; 10(24):10940-10956. doi:10.7150/thno.45207. https://www.thno.org/v10p10940.htm

Other styles

Abstract

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance.

Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms.

Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization.

Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.

Keywords: Triple-negative breast cancer, paclitaxel resistance, SYTL4, microtubule polymerization

Citation styles

APA

Liu, X.Y., Jiang, W., Ma, D., Ge, L.P., Yang, Y.S., Gou, Z.C., Xu, X.E., Shao, Z.M., Jiang, Y.Z. (2020). SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer. Theranostics, 10(24), 10940-10956. https://doi.org/10.7150/thno.45207.

ACS

Liu, X.Y.; Jiang, W.; Ma, D.; Ge, L.P.; Yang, Y.S.; Gou, Z.C.; Xu, X.E.; Shao, Z.M.; Jiang, Y.Z. SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer. Theranostics 2020, 10 (24), 10940-10956. DOI: 10.7150/thno.45207.

NLM

CSE

Liu XY, Jiang W, Ma D, Ge LP, Yang YS, Gou ZC, Xu XE, Shao ZM, Jiang YZ. 2020. SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer. Theranostics. 10(24):10940-10956.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.