Hypoxia-induced LncRNA DACT3-AS1 upregulates PKM2 to promote metastasis in hepatocellular carcinoma through the HDAC2/FOXA3 pathway

Wang, Liyan; Li, Bin; Xiao-tong, BO; Yi, Xiaoyuan; Xiao, Xuejun; Zheng, Qianqian

doi:10.1038/s12276-022-00767-3

Cited by 24 publications

(16 citation statements)

References 56 publications

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“…Third, hypoxia can transcriptionally induce HIF1α to promote YTHDF1 expression, which enhances PKM2 expression and increases tumorigenesis 72 . Fourth, hypoxia-induced LncRNA DACT3-AS1 upregulates PKM2 expression to promote HCC metastasis through the HDAC2/FOXA3 pathway 73 . These findings, as evidenced by ours and others 74 , solidly indicate that hypoxia-triggered overexpression and translocation of PKM2 in HCC cells is a potential target for Ab-based therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Wang,

Qi,

Chen

et al. 2024

Int. J. Biol. Sci.

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Background: Hypoxia induces hepatocellular carcinoma (HCC) malignancies; yet it also offers treatment opportunities, exemplified by developing hypoxia-activated prodrugs (HAPs). Although HAP TH-302 combined with therapeutic antibody (Ab) has synergistic effects, the clinical benefits are limited by the on-target off-tumor toxicity of Ab. Here, we sought to develop a hypoxia-activated anti-M2 splice isoform of pyruvate kinase (PKM2) Ab combined with TH-302 for potentiated targeting therapy. Methods: Codon-optimized and hypoxia-activation strategies were used to develop H103 Ab-azo-PEG5k (HAP103) Ab. Hypoxia-activated HAP103 Ab was characterized, and hypoxia-dependent antitumor and immune activities were evaluated. Selective imaging and targeting therapy with HAP103 Ab were assessed in HCC-xenografted mouse models. Targeting selectivity, systemic toxicity, and synergistic therapeutic efficacy of HAP103 Ab with TH-302 were evaluated. Results: Human full-length H103 Ab was produced in a large-scale bioreactor. Azobenzene (azo)-linked PEG5k conjugation endowed HAP103 Ab with hypoxia-activated targeting features. Conditional HAP103 Ab effectively inhibited HCC cell growth, enhanced apoptosis, and induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) functions. Analysis of HCC-xenografted mouse models showed that HAP103 Ab selectively targeted hypoxic HCC tissues and induced potent tumor-inhibitory activity either alone or in combination with TH-302. Besides the synergistic effects, HAP103 Ab had negligible side effects when compared to parent H103 Ab. Conclusion: The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Wang,

Qi,

Chen

et al. 2024

Int. J. Biol. Sci.

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“…Several lncRNAs associated with cell metabolism that promote HCC were recently reported, such as lncRNA RP11-386G11. 10 [41], SNHG6 [42], FASRL [43], and DACT3-AS1 [44].…”

Section: Lncrnas Promote the Progression Of Hccmentioning

confidence: 99%

The expression and function of long noncoding RNAs in hepatocellular carcinoma

Du,

Su,

Gao

et al. 2023

Cancer Innovation

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With the deepening of the genome project study, attention on noncoding RNAs is increasing. Long noncoding RNAs (lncRNAs) have become a new research hotspot. A growing number of studies have revealed that lncRNAs are involved in tumorigenesis and tumor suppressor pathways. Aberrant expressions of lncRNAs have been found in a variety of human tumors including hepatocellular carcinoma (HCC). In this review, we provide a brief introduction to lncRNA and highlight recent research on the functions and clinical significance of lncRNAs in HCC.

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“…HDAC2 has been reported to participate in regulating tumor proliferation and apoptosis, while research about its function in CRC development was rare [21][22][23]. HDAC2 was found to be highly expressed in tumor tissue and patients with higher expression tend to have an unfavorable prognosis (Fig.…”

Section: The Upregulated Hdac2 In Crc Can Suppress the Transcriptiona...mentioning

confidence: 99%

PJA2 suppresses colorectal cancer progression by controlling HDAC2 degradation and stability.

Chen,

Yang,

Jin

et al. 2023

Preprint

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Background The Praja Ring Finger Ubiquitin Ligase 2 (PJA2), one of the RING ligase family, has been reported to be degrading differential substrates and regulating diverse diseases. However, the E3 ligase function of PJA2 played in cancer development and progression, especially in colorectal cancer, is still almost unknown. Methods The correlation between PJA2 and clinical characteristics was explored through the TCGA and GEO data sets. The qRT-PCR and Immunohistochemical assays were employed to assess the expression of PJA2 in CRC tissues and cell lines. The biological functions of PJA2 were verified by cell counting kit-8, colony formation, flow cytometry, cell-derived xenograft, AOM/DSS colorectal tumorigenesis model and other in vivo and in vitro experiments. The RNA-seq, mass spectrometry analysis, GST pull-down, Chromatin Immunoprecipitation and Immunofluorescence were utilized to disclose the underlying molecular mechanisms of PJA2 in CRC proliferation and apoptosis. Results Our research discovered that PJA2 was abnormally downregulated in CRC tissues and cell lines, and the lower expression of PJA2 was detected, the poorer prognosis was present. Functionally, further in vivo and in vitro experiments jointly uncovered that PJA2 acted as a tumor suppressor gene via inhibiting tumor proliferation and promoting cancer cell apoptosis in CRC progression. Regarding mechanism, PJA2 could recognize HDAC2 through the RBD domain and bind with the N-terminal of HDAC2 to ubiquitinate and degrade HDAC2 at K90 residue. PJA2-mediated ubiquitination and degradation of HDAC2 could counteract the transcriptional suppression of the IFIT family and PJA2, thus facilitating the transcription of the IFIT family to promote cancer cell apoptosis and inhibit tumor proliferation. Conclusion Our data showed that PJA2 interacted with HDAC2, promoted the poly-ubiquitination and degradation of HDAC2, abrogated the transcriptional suppression of the IFIT family and PJA2, constituted a positive feedback loop, and prevented tumor proliferation. Hence, PJA2 might be a potential therapeutic target for CRC, and interruption of this positive feedback loop would be a treatment strategy to slow or restrain the progression of CRC.

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Hypoxia-induced LncRNA DACT3-AS1 upregulates PKM2 to promote metastasis in hepatocellular carcinoma through the HDAC2/FOXA3 pathway

Cited by 24 publications

References 56 publications

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma

The expression and function of long noncoding RNAs in hepatocellular carcinoma

PJA2 suppresses colorectal cancer progression by controlling HDAC2 degradation and stability.

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