CAFs-derived lactate enhances the cancer stemness through inhibiting the MST1 ubiquitination degradation in OSCC

Shuzhen Zhang; Jingjing Wang; Yang Chen; Weilian Liang; Hanzhe Liu; Ruixue Du; Yunqing Sun; Chuanyu Hu; Zhengjun Shang

doi:10.1186/s13578-024-01329-y

CAFs-derived lactate enhances the cancer stemness through inhibiting the MST1 ubiquitination degradation in OSCC

Cell Biosci. 2024 Nov 27;14(1):144. doi: 10.1186/s13578-024-01329-y.

Authors

Shuzhen Zhang^#^{1

2}, Jingjing Wang^#¹, Yang Chen^#^{1

3}, Weilian Liang^{1

4}, Hanzhe Liu¹, Ruixue Du¹, Yunqing Sun¹, Chuanyu Hu^{5

6

7}, Zhengjun Shang^{8

9}

Affiliations

¹ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
² Central Department School & Hospital of Stomatology, Wuhan University, Wuhan, 430022, China.
³ Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
⁴ Day Surgery Center, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
⁵ Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. chuanyuhu@hust.edu.cn.
⁶ School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chuanyuhu@hust.edu.cn.
⁷ Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China. chuanyuhu@hust.edu.cn.
⁸ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China. shangzhengjun@whu.edu.cn.
⁹ Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China. shangzhengjun@whu.edu.cn.

^# Contributed equally.

PMID: 39605072
DOI: 10.1186/s13578-024-01329-y

Abstract

Background: Cancer-associated fibroblasts (CAFs), a predominant stromal cell type in the tumor microenvironment, significantly affect the progression of oral squamous cell carcinoma (OSCC).

Results: The specific mechanisms through which CAFs influence the cancer stem cell phenotype in OSCC are not fully understood. This study explored the effects of lactic acid produced by CAFs on the cancer stem cells (CSCs) phenotype of OSCC cells. Our results demonstrated that CAFs exhibit increased glycolysis and lactic acid production. Lactic acid treatment enhances CSCs-related markers expression, sphere formation, and clonogenic ability of OSCC cells. RNA sequencing revealed that lactic acid treatment elevates Discs Large Homolog 5 (DLG5) expression and markedly affects the Hippo pathway. Further investigation revealed that DLG5 mediates the effects of lactic acid on the CSCs phenotype. DLG5 knockdown results in elevated expression of E3 ubiquitin ligase Cullin 3, which can promote the ubiquitination and degradation of MST1, but the expression of phosphorylated MST1 remains unchanged. This leads to enhanced binding of phosphorylated MST1 to YAP1, increasing YAP1 phosphorylation and activating the Hippo pathway.

Conclusion: Collectively, our findings suggest that lactic acid from CAFs promotes the CSCs phenotype in OSCC through the DLG5/CUL3/MST1 axis. Therefore, targeting lactic acid exchange between CAFs and tumor cells may provide a novel therapeutic approach to suppress the CSCs phenotype in OSCC.

Keywords: Cancer stem cells; DLG5; Hippo pathway; Lactate; Ubiquitination.

Abstract

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