HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis

Lai, Hui Huang; Li, Jie Ning; Wang, Ming Yang; Huang, Hsin Yi; Croce, Carlo M.; Sun, Hui; Lyu, Yu Jhen; Kang, Jui Wen; Chiu, Ching-Feng; Hung, Mien‐Chie; Suzuki, Hiroshi; Chen, Pai Sheng

doi:10.1172/jci89212

Cited by 56 publications

(57 citation statements)

References 70 publications

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“…The increased miR-423-5p inhibits the cell cycle and promotes autophagy activity (Stiuso et al, 2015). The miRNA biogenesis factors Dicer and Ago2 are degraded by autophagy through recognition of the autophagy receptor to promote cancer progression (Gibbings et al, 2012;Lai et al, 2018). Both Dicer and Ago2 are ubiquitylated through an E3 ligase to specifically interact with the autophagy receptor.…”

Section: Discussionmentioning

confidence: 99%

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Lai

Hong

et al. 2019

Molecular Oncology

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Hepatocellular carcinoma ( HCC ) is a lethal human malignancy and a leading cause of cancer‐related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first‐line treatment for patients with advanced HCC . However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA ‐binding protein 2 (TARBP2) is a multifaceted mi RNA biogenesis factor that regulates cancer stem cell ( CSC ) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP 2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP 2 is significantly downregulated in sorafenib‐resistant HCC cells. The TARBP 2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel mi RNA ‐independent role of TARBP 2 in regulating sorafenib resistance in HCC cells.

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Section: Discussionmentioning

confidence: 99%

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Lai

Hong

et al. 2019

Molecular Oncology

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“…Loss of p53 function and mutations in the p53 gene are notably the cause for the incidence and progression of many different cancers by supporting cell proliferation and survival, metabolism, genome instability, pro-survival autophagy, and metastasis in addition to conferring therapeutic resistance to cancer cells [84][85][86]. The RNase enzyme, DICER, that is important in processing the formation of function micro-RNAs (miRNA) was frequently downregulated in human cancers and was linked to cancer progression and cancer metastasis [87][88][89].…”

Section: Biology Of Metformin and Molecular Mechanism Of Actionmentioning

confidence: 99%

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

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Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

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“…Apart from our results, transcriptional inhibition of DICER1 under hypoxia has been observed in several studies. 5,8,9,10 We discovered that DICER protein stability is decreased in HIF-1αoverexpressing cells under both hypoxic and nonhypoxic stimulation. However, alternation of DICER1 mRNA levels was only observed under hypoxic conditions, suggesting the existence of another regulatory pathway leading to suppressing transcriptional levels of DICER1.…”

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confidence: 97%

“…We first identified DICER as a novel hypoxia-inducible factor-1α (HIF-1α)-binding protein. 5 HIF-1α, as its name implies, is a critical oxygen-sensitive transcription factor induced and stabilized under hypoxic conditions. Tissue hypoxia is a microenvironmental feature under inadequate oxygen supply in a region of the body.…”

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confidence: 99%

“…Our findings identify a noncanonical oncogenic role of HIF-1α in suppressing miRNA biogenesis by facilitating the binding of PARKIN and DICER, whereby ubiquitinated DICER is selectively degraded through autophagy ( Figure 1). 5 Recent study revealed that PARKIN is a novel E3 ligase for ubiquitination of HIF-1α. Ubiquitinated HIF-1α is further degraded by proteasome to inhibit cancer metastasis, suggesting that PARKIN serves as a tumor suppressor during cancer progression.…”

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confidence: 99%

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Dual mechanism of DICER downregulation facilitates cancer metastasis

Lai

Chen

2018

Molecular & Cellular Oncology

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Although downregulation of DICER - a critical enzyme in microRNA (miRNA) maturation - reportedly promotes cancer metastasis, understanding of its upstream regulators remains limited. Our recent study demonstrated a noncanonical oncogenic effect of hypoxia-inducible factor-1α (HIF-1α), which directly binds with DICER to promote PARKIN-mediated autophagic-lysosomal proteolysis and consequently suppresses miRNA biogenesis, facilitating metastasis.

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HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis

Cited by 56 publications

References 70 publications

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

TARBP2‐mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Dual mechanism of DICER downregulation facilitates cancer metastasis

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