2. Academic Validation
  3. FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma

FOXA1 prevents nutrients deprivation induced autophagic cell death through inducing loss of imprinting of IGF2 in lung adenocarcinoma

  • Cell Death Dis. 2022 Aug 16;13(8):711. doi: 10.1038/s41419-022-05150-8.
Junjun Li  # 1 2 3 4,  Yongchang Zhang  # 1 2 3 4,  Li Wang 5,  Min Li 6,  Jianbo Yang 7,  Pan Chen 1,  Jie Zhu 1 2 3 4,  Xiayu Li 4,  Zhaoyang Zeng 1 2 3 4,  Guiyuan Li 1 2 3 4,  Wei Xiong 1 2 3 4,  James B McCarthy 7,  Bo Xiang 8 9 10 11,  Mei Yi 12
Affiliations

Affiliations

  • 1 Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
  • 2 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China.
  • 3 The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China.
  • 4 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
  • 5 Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
  • 6 Department of Respiratory Medicine, Xiangya Lung Cancer Center; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 7 Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 8 Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China. xiangbolin@csu.edu.cn.
  • 9 The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410008, Hunan, China. xiangbolin@csu.edu.cn.
  • 10 The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China. xiangbolin@csu.edu.cn.
  • 11 Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. xiangbolin@csu.edu.cn.
  • 12 Department of Respiratory Medicine, Xiangya Lung Cancer Center; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. yi_mei@csu.edu.cn.
  • # Contributed equally.
PMID: 35974000 DOI: 10.1038/s41419-022-05150-8
Abstract

Lung Cancer remains one of the most common malignancies and the leading cause of cancer-related death worldwide. Forkhead box protein A1 (FOXA1) is a pioneer factor amplified in lung adenocarcinoma (LUAD). However, its role in LUAD remains elusive. In this study, we found that expression of FOXA1 enhanced LUAD cell survival in nutrients deprived conditions through inhibiting autophagic cell death (ACD). FOXA1 bound to the imprinting control region of insulin-like growth factor 2 (IGF2) and interacted with DNA Methyltransferase 1 (DNMT1), leading to initiation of DNMT1-mediated loss of imprinting (LOI) of IGF2 and autocrine of IGF2. Blockage of IGF2 and its downstream insulin-like growth factor 1 receptor (IGF1R) abolished the protective effect of FOXA1 on LUAD cells in nutrients deprived conditions. Furthermore, FOXA1 suppressed the expression of the lysosomal Enzyme glucocerebrosidase 1 (GBA1), a positive mediator of ACD, through ubiquitination of GBA1 enhanced by IGF2. Notably, FOXA1 expression in A549 cells reduced the efficacy of the anti-angiogenic drug nintedanib to inhibit xenograft tumor growth, whereas a combination of nintedanib with IGF1R inhibitor linsitinib or mTORC1 Inhibitor rapamycin enhanced tumor control. Clinically, high expression level of FOXA1 protein was associated with unfavorable prognosis in LUAD patients of advanced stage who received bevacizumab treatment. Our findings uncovered a previously unrecognized role of FOXA1 in mediating loss of imprinting of IGF2, which confer LUAD cells enhanced survival ability against nutrients deprivation through suppressing autophagic cell death.

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