KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis

Yang, Shaoshan; Ren, Xiaohu; Liang, Yongquan; Yan, Yongmin; Zhou, Yingwu; Hu, Jinlong; Wang, Zhizhi; Song, Fuyao; Wang, Feifei; Liao, Wangjun; Liao, Wenting; Ding, Yan‐Qing; Li, Liang

doi:10.1038/s41388-019-0978-0

Cited by 48 publications

(36 citation statements)

References 39 publications

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“…Therefore, HSP40 seems to be a promising therapeutic target in the fight against CSCs. The described effects of KNK437 [134] and the OSU-03012/sildenafil combination [100] are the "proof-of-principle" that HSP40 can be significantly diminished by means of small molecule inhibitors. Therefore, such inhibitors have to be developed and tested in CSC-related models.…”

Section: Hsp40mentioning

confidence: 97%

“…Although KNK437, a benzylidene lactam compound, is known as an inhibitor of the HSF1-mediated expression of all inducible HSPs [133], Yang et al revealed that in colorectal cancer, this inhibitor dramatically decreased the level of DnaJA1 (a member of the HSP40 family), while only slightly affecting the levels of other HSPs [134]. In this study, KNK437 reduced metastasis formation, which allowed the authors to suggest an important role of DnaJA1 in promoting the pro-metastatic (CSC-like) phenotype development.…”

Section: Hsp40mentioning

confidence: 99%

“…Similarly, the activating phosphorylation of HSF1 at serine 326 was shown to be critical for the maintenance of gynecologic CSCs, although the researchers explained the effect of the HSF1 activation-triggered induction of HSP27 [171]. However, not HSP27 but members of the HSP40 family, DNAJB8 [131] and DNAJA1 [134], were determined as the critical products of the heat-induced HSF1 activation/HSP expression pathway that conferred the cancer stemness-like properties. Despite some discrepancy (HSP27 vs. HSP40), HSF1 activation and subsequent expression of inducible chaperones (HSPs) in tumor cells clearly promote the CSC phenotype's acquisition.…”

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Hsp40mentioning

confidence: 97%

Section: Hsp40mentioning

confidence: 99%

Section: Hsf1 and Hsf1-activating Exposurementioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…Clinicopathologic analyses have shown the markedly increased expression of DnaJA1 in colorectal cancer (CRC) tissues, particularly those of which had developed metastases in lymph node and distant organs. Investigating the functional mechanism of HSP40 in cancer, Yang et al demonstrated that Hsp40 DNAJ member A1 (DnaJA1) is transcribed by E2F transcription factor 1 and promotes cell cycle progression by inhibiting ubiquitin degradation of cell division cycle protein 45 (CDC45) in CRC [32]. DNAJ member B6 (DnaJB6) has also been elucidated as a poor prognostic factor for CRC patients, where its overexpression was observed in 39% of the CRC patients, especially in those at the stage of cancer IV compared to the stages I-III.…”

Section: Oncogenic Role Of Hsp40 In Proliferation and Metastasis Of Cmentioning

confidence: 99%

“…KNK437, a benzylidene lactam compound and a pan-HSP inhibitor, inhibits the expression of HSPs, which are HSP27, HSP40, HSP 72, and HSP110 [165]. Treatment of colorectal cancer cells with KNK437 inhibits the expression of DnaJA1 and the cell cycle progression through destabilization of CDC45 [32]. As DnaJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling, knockdown of DnaJB1 promotes the sensitivity of tumor cells to anti-cancer effects of the EGFR inhibitor gefitinib in human lung epithelial adenocarcinoma cells [31].…”

Section: Hsp40 Inhibition For Cancer Therapymentioning

confidence: 99%

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Yun

Kim

Lim

et al. 2019

Cells

198

158

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Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

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Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo‐Independent Regulation of Heat Shock Protein 70 Family Members

et al. 2021

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Transcriptional enhancer factor domain family member 4 (TEAD4) is a downstream effector of the conserved Hippo signaling pathway, regulating the expression of genes involved in cell proliferation and differentiation. It is up‐regulated in several cancer types and is associated with metastasis and poor prognosis. However, its role in hepatocellular carcinoma (HCC) remains largely unexplored. Using data from The Cancer Genome Atlas, we found that TEAD4 was overexpressed in HCC and was associated with aggressive HCC features and worse outcome. Overexpression of TEAD4 significantly increased proliferation and migration rates in HCC cells in vitro as well as tumor growth in vivo. Additionally, RNA sequencing analysis of TEAD4‐overexpressing HCC cells demonstrated that TEAD4 overexpression was associated with the up‐regulation of genes involved in epithelial‐to‐mesenchymal transition, proliferation, and protein‐folding pathways. Among the most up‐regulated genes following TEAD4 overexpression were the 70‐kDa heat shock protein (HSP70) family members HSPA6 and HSPA1A. Chromatin immunoprecipitation–quantitative real‐time polymerase chain reaction experiments demonstrated that TEAD4 regulates HSPA6 and HSPA1A expression by directly binding to their promoter and enhancer regions. The pharmacologic inhibition of HSP70 expression in TEAD4‐overexpressing cells reduced the effect of TEAD4 on cell proliferation. Finally, by overexpressing TEAD4 in yes‐associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ)‐knockdown HCC cells, we showed that the effect of TEAD4 on cell proliferation and its regulation of HSP70 expression does not require YAP and TAZ, the main effectors of the Hippo signaling pathway. Conclusion: A novel Hippo‐independent mechanism for TEAD4 promotes cell proliferation and tumor growth in HCC by directly regulating HSP70 family members.

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KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis

Cited by 48 publications

References 39 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo‐Independent Regulation of Heat Shock Protein 70 Family Members

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