Identification of potential target genes associated with the reversion of androgen-dependent skeletal muscle atrophy

Coelho, Priscila de O.; Guarnier, Flávia Alessandra; Figueiredo, Leonardo Bruno; Pacini, Enio Setsuo Arakaki; Godinho, Rosely Oliveira; Gomes, Marcelo D.

doi:10.1016/j.abb.2019.01.009

Cited by 8 publications

(6 citation statements)

References 56 publications

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“…[4,39] Currently, the specific roles of each member in KLHLs are unknown. As a member of the KLHL family, KLHL38 regulates the Akt signaling pathway [23] and may be used as a prognostic marker for lung adenocarcinoma and squamous cell carcinoma [25] . Recent publications also suggested a functional link between KLHL38 and clinical diseases, particularly cancer.…”

Section: Discussionmentioning

confidence: 99%

“…[5] KLHL38, an atrophy reversion-related gene, has been found to be down-regulated in the Levator ani muscle after androgen treatment using an androgen deprivation model. [23] In addition, KLHL38 is highly expressed in heart tissue of heart failure patients and it leads to cardiac apoptosis by promoting ubiquitination of myocardin. [24] It was reported that the overexpression of KLHL38 may indicate a poor prognosis for patients with non-small cell lung carcinoma (NSCLC) [25] and triple-negative breast cancer (TNBC) [26] due to its aggravated tumor behavior .…”

Section: Introductionmentioning

confidence: 99%

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A Pan-cancer Analysis of Kelch Like Family Member 38 (KLHL38) Alterations in Human Cancers

Hai,

Liu,

Meng

et al. 2024

Preprint

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Background: Growing evidence suggests that the KLHL family may be involved in the occurrence and development of cancer. KLHL38, a member of the KLHL protein family, contains BTB/POZ, BACK domains, and five to six Kelch motifs. However, no pan-cancer analyses have been conducted on KLHL38. In this study, we aimed to explore the potential biological functions of KLHL38 that may provide potential tumor-related therapeutic targets. Methods: The potential roles of KLHL38 in different tumor types were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. Several factors related to KLHL38 were analyzed, including expression differences, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), tumor microenvironment (TME), stemness score, and immune cell infiltration. Results: There were significant differences in KLHL38 expression among different cancer types and between cancer tissue and normal tissue, which was closely correlated with survival prognosis. Furthermore, KLHL38 expression was found to be correlated with DNA methylation, tumor mutations, and stemness scores in major cancer types, suggesting its involvement in cancer development. To some extent, KLHL38 expression levels were significantly correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes. These results indicated that KLHL38 can be used as a tumor prognostic indicator. Conclusion: In our study, we analyzed the role of KLHL38 role in tumor development and immunotherapy, which may provide a potential new target for tumor treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Pan-cancer Analysis of Kelch Like Family Member 38 (KLHL38) Alterations in Human Cancers

Hai,

Liu,

Meng

et al. 2024

Preprint

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“…FBXO32 is well known for its major role in SkM atrophy [56]. In a rat castration-reversal model of muscle atrophy, Klhl38 was upregulated while its neighbor Fbxo32 was downregulated [37]. However, in humans, both genes have their highest expression in normal SkM and their intragenic and intergenic enhancer chromatin could positively interact with each other (Figure 2B, Supplemental Figure 8).…”

Section: Discussionmentioning

confidence: 99%

“…KLHL30, a gene that has not been the focus of any published articles, is much more highly expressed in SkM than in any other tissue and has higher expression in myoblasts and myotubes than in non-muscle cell cultures (Table 1). Its high expression in SkM is associated with a SkM-specific super-enhancer (Figure 2A There is an intriguing relationship between KLHL30 and KLHL38, another little studied gene that may help to reverse muscle atrophy [37]. Most of the open reading frame (ORF) of KLHL38 is in exon 2 and is largely derived from a retrotransposed copy (retrogene) of coding sequences in exon 2 of KLHL30 (Figure 2A and B).…”

Section: Skeletal Muscle-specific Expression Promoter Chromatin and Enhancer Chromatin In Klhl30 And In Klhl38 A Paralog That Contains A mentioning

confidence: 99%

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

Ehrlich

Baribault

Ehrlich

2020

Preprint

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KLHL genes and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in normal cell function and in disease (KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies that examined epigenetic factors affecting transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in a super-enhancer. The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence that gene neighbors (HHATL and FBXO32) of KLHL40 and KLHL38 harbor enhancer chromatin that likely upregulates the adjacent KLHL gene. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5’ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3’ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5’ ends of genes in studies of normal and abnormal gene regulation.

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“…KLHL38 is a member of the KLHL family and contains a BTB domain, a back domain, and six kelch domains 15 .KLHL38 expression is reportedly upregulated during diapause and downregulated after androgen treatment during the reversal of androgen-dependent skeletal muscle atrophy, in which the Akt signaling pathway is involved 16 . Using database mining ( http://www.proteinatlas.org/ ) and analysis, KLHL38 may be a potential indicator for prognosis of lung adenocarcinoma and squamous cell carcinoma.…”

Section: Introductionmentioning

confidence: 99%

KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway

Wang

Jiang

et al. 2021

Cell Death Dis

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Lung cancer is the leading cause of cancer-related death worldwide. KLHL38 has been reported to be upregulated during diapause but downregulated after androgen treatment during the reversal of androgen-dependent skeletal muscle atrophy. This study aimed to clarify the role of KLHL38 in non-small cell lung cancer (NSCLC). KLHL38 expression was evaluated in tumor and adjacent normal tissues from 241 patients with NSCLC using immunohistochemistry and real-time PCR, and its association with clinicopathological parameters was analyzed. KLHL38 levels positively correlated with tumor size, lymph node metastasis, and pathological tumor-node-metastasis stage (all P < 0.001). In NSCLC cell lines, KLHL38 overexpression promoted PTEN ubiquitination, thereby activating Akt signaling. It also promoted cell proliferation, migration, and invasion by upregulating the expression of genes encoding cyclin D1, cyclin B, c-myc, RhoA, and MMP9, while downregulating the expression of p21 and E-cadherin. In vivo experiments in nude mice further confirmed that KLHL38 promotes NSCLC progression through Akt signaling pathway activation. Together, these results indicate that KLHL38 is a valuable candidate prognostic biomarker and potential therapeutic target for NSCLC.

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Identification of potential target genes associated with the reversion of androgen-dependent skeletal muscle atrophy

Cited by 8 publications

References 56 publications

A Pan-cancer Analysis of Kelch Like Family Member 38 (KLHL38) Alterations in Human Cancers

A Pan-cancer Analysis of Kelch Like Family Member 38 (KLHL38) Alterations in Human Cancers

Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes

KLHL38 involvement in non-small cell lung cancer progression via activation of the Akt signaling pathway

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