Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
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Research Article Oncology

Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC

Abstract

Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating studies have implicated the metabolic reprogramming of CSCs, mitochondrial dynamics in such cells remain poorly understood. Here we pinpointed OPA1hi with mitochondrial fusion as a metabolic feature of human lung CSCs, licensing their stem-like properties. Specifically, human lung CSCs exerted enhanced lipogenesis, inducing OPA1 expression via transcription factor SAM Pointed Domain containing ETS transcription Factor (SPDEF). In consequence, OPA1hi promoted mitochondrial fusion and stemness of CSCs. Such lipogenesishi, SPDEFhi, and OPA1hi metabolic adaptions were verified with primary CSCs from lung cancer patients. Accordingly, blocking lipogenesis and mitochondrial fusion efficiently impeded CSC expansion and growth of organoids derived from patients with lung cancer. Together, lipogenesis regulates mitochondrial dynamics via OPA1 for controlling CSCs in human lung cancer.

Authors

Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen

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Figure 9

SPDEF drives the transcription of OPA1 in CSCs.

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SPDEF drives the transcription of OPA1 in CSCs. (A) A549 tumor spheres w...
(A) A549 tumor spheres with or without SPDEF overexpression were treated in the presence or absence of C75 (50 μM) and were monitored for OPA1 expressions. Representative and mean ± SEM from 5–10 independent experiments. (B) OPA1 promoter occupancy by SPDEF determined by ChIP and qPCR in A549 tumor spheres. Mean ± SEM from 8 independent experiments. (C and D) A549 tumor spheres and adherent cells were detected for expression of SPDEF by qPCR and immunoblots. Representative and mean ± SEM from 6 independent experiments. (E and F) A549 tumor spheres with or without SPDEF knockdown were detected for OPA1 expression by either qPCR or immunoblot. Representative and mean ± SEM from 10 independent experiments. (G) A549 tumor spheres with or without SPDEF knockdown were detected for ALDH1 and OCT4 expression by qPCR. Mean ± SEM from 12 independent experiments. (H and I) Experiments using a second SPDEF siRNA and the reintroduction of SPDEF by overexpression confirmed the crucial role of SPDEF in regulating expressions of OPA1 and stem-related genes in A549 tumor spheres. Mean ± SEM from 8–9 independent experiments. (J) The G1 and G2 SPDEF–depleted A549 tumor spheres were analyzed for sphere formations. Mean ± SEM from 6 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 with paired t test (B–G and J) and ANOVA plus Tukey’s method (A, H, and I).