SOX1 Functions as a Tumor Suppressor by Repressing HES1 in Lung Cancer

Shan-Yueh Chang; Ti-Hui Wu; Yu-Lueng Shih; Ying-Chieh Chen; Her-Young Su; Chih-Feng Chian; Ya-Wen Lin

doi:10.3390/cancers15082207

SOX1 Functions as a Tumor Suppressor by Repressing HES1 in Lung Cancer

Cancers (Basel). 2023 Apr 8;15(8):2207. doi: 10.3390/cancers15082207.

Authors

Shan-Yueh Chang^{1

2}, Ti-Hui Wu³, Yu-Lueng Shih⁴, Ying-Chieh Chen², Her-Young Su¹, Chih-Feng Chian², Ya-Wen Lin^{1

5

6}

Affiliations

¹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
² Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
³ Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
⁴ Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
⁵ Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan.
⁶ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.

Abstract

The development of lung cancer is a complex process that involves many genetic and epigenetic changes. Sex-determining region Y (SRY)-box (SOX) genes encode a family of proteins that are involved in the regulation of embryonic development and cell fate determination. SOX1 is hypermethylated in human cancers. However, the role of SOX1 in the development of lung cancer is unclear. We used quantitative methylation-specific polymerase chain reaction (MSP), quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, and web tools to confirm the frequent epigenetic silencing of SOX1 in lung cancer. Stable overexpression of SOX1 repressed cell proliferation, anchorage-independent growth, and invasion in vitro as well as cancer growth and metastasis in a xenograft mouse model. Knockdown of SOX1 by the withdrawal of doxycycline partly restored the malignant phenotype of inducible SOX1-expressing NSCLC cells. Next, we discovered the potential downstream pathways of SOX1 using RNA-seq analysis and identified HES1 as a direct target of SOX1 using chromatin immunoprecipitation (ChIP)-PCR. Furthermore, we performed phenotypic rescue experiments to prove that overexpression of HES1-FLAG in SOX1-expressing H1299 cells partly reversed the tumor-suppressive effect. Taken together, these data demonstrated that SOX1 acts as a tumor suppressor by directly inhibiting HES1 during the development of NSCLC.

Keywords: HES1; SOX1; lung cancer; tumor suppressor.

Grants and funding

This work was supported in part by the following grants: MOST 110-2314-B-016-041 and MOST 105-2320-B-016-017-MY3 from the Ministry of Science and Technology, Taiwan, Republic of China; MND-MAB-110-009, MND-MAB-110-010, MND-MAB-110-011, MND-MAB-C01-111001, MND-MAB-C01-111002, and MND-MAB-C01-111003 from the Ministry of National Defense, Taiwan, Republic of China; TSGH-E-110215, TSGH-E-111234, TSGH-E-111236, TSGH-D-112103, and TSGH-E-112237 from Tri-Service General Hospital, Taiwan, Republic of China; The Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China.