YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

Jin, Lan; Chen, Yunhe; Cheng, Dan; He, Zhikai; Shi, Xinyi; Du, Bin; Xi, Xueyan; Gao, Yujing; Guo, Yang

doi:10.1038/s41419-021-03722-8

Cited by 61 publications

(36 citation statements)

References 26 publications

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“…The depletion of CRB3 can inhibit the Hippo pathway and lead to increased nuclear localization of YAP [ 30 , 31 , 43 ]. The Hippo pathway plays a crucial role in regulating CRC progression [ 44 – 47 ]. In the present study, we also observed that CRB3 knockdown inhibited the Hippo pathway and increased the nuclear localization of YAP, suggesting that CRB3 regulates CRC progression through the Hippo pathway.…”

Section: Discussionmentioning

confidence: 99%

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Pan

Liu

Xiao

et al. 2022

J Exp Clin Cancer Res

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Background Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. Methods Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. Results M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain–containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. Conclusions M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A–CRB3–Hippo pathway.

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Section: Discussionmentioning

confidence: 99%

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Pan

Liu

Xiao

et al. 2022

J Exp Clin Cancer Res

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“…In colorectal cancer, aberrant signals from cancer-associated pathways, such as WNT and activated KRAS, activate Hippo to promote tumor growth and metastasis [ 28 ]. It is intriguing that the apoptosis inhibitor BCL2 is among the target genes of YAP1, a fact that could contribute to YAP1 dependency in 20q11.21 amplified cancers, given that the related BCL2L1 protein is dysregulated in these cancers [ 29 ]. Thus, interruption of Hippo signaling could impede, at least partially, aberrant cancer cell signals.…”

Section: Discussionmentioning

confidence: 99%

Cell Models for Chromosome 20q11.21 Amplification and Drug Sensitivities in Colorectal Cancer

Voutsadakis

2021

Medicina

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Background and objectives: The chromosome locus 20q11.21 is a commonly amplified locus in colorectal cancer, with a prevalence of 8% to 9%. Several candidate cancer-associated genes are transcribed from the locus. The therapeutic implications of the amplification in colorectal cancer remain unclear. Materials and Methods: Preclinical cell line models of colorectal cancer included in the Cancer Cell Line Encyclopedia (CCLE) collection were examined for the presence of amplifications in 20q11.21 genes. Correlations of the presence of 20q11.21 amplifications with gene essentialities and drug sensitivities were surveyed on salient databases for determination of therapeutic leads. Results: A significant subset of colorectal cancer cell lines in the CCLE (12 of 63 cell lines, 19%) bear amplifications of genes located at 20q11.21. Cancer-associated genes of the locus include ASXL1, DNMT3B, BCL2L1, TPX2, KIF3B and POFUT1. These genes are all amplified in the 12 cell lines, but they are variably over-expressed at the mRNA level, compared to non-amplified lines. 20q11.21 amplified cell lines are sensitive to various tyrosine kinase inhibitors and are resistant to chemotherapy drugs targeting the mitotic apparatus and microtubules. CRISPR and RNAi dependencies screening revealed, besides the β-catenin and KRAS genes, a few recurrent gene dependencies in more than one cell line, including YAP1 and JUP. Conclusions: Cell line models of colorectal cancer with 20q11.21 gene amplifications display dependencies on the presence of specific genes and resistance or sensitivity to specific drugs and drug categories. Observations from in vitro models may form the basis for clinical drug development in this subtype of colorectal cancer. Genetic lesions conferring synthetic lethality to certain drugs or categories of drugs could be discovered with this approach.

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“…Additionally, Bcl-2 family proteins inhibit VSP34-BECN1 complex activation [ 56 ]. A recent paper demonstrated in a colorectal carcinoma (CRC) model that the YAP/TEAD complex binds to upregulate Bcl-2 expression, which leads to autophagy inhibition [ 57 ]. This suggests that additional pathways may play a role in autophagy regulation.…”

Section: Autophagymentioning

confidence: 99%

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

Wang

Golino

Xie

2022

Cancers

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Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.

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YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

Cited by 61 publications

References 26 publications

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Cell Models for Chromosome 20q11.21 Amplification and Drug Sensitivities in Colorectal Cancer

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

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