P/CAF rescues the Bhlhe40-mediated repression of MyoD transactivation

Hsiao, Sheng Pin; Huang, Kai; Chang, Hsin; Chen, Shen L.

doi:10.1042/bj20090072

Cited by 20 publications

(34 citation statements)

References 42 publications

(62 reference statements)

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“…7E). As reported previously, BHLHE40/41 expression recruited HDAC1 and excluded KAT2B and acetylated histone H3 from the SBS (11,40,41) (Fig. 7E).…”

Section: Clinical Evaluation Of Bhlhe40 and Bhlhe41 Expression In Hecmentioning

confidence: 56%

Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Asanoma

Liu

Yamane

et al. 2015

Molecular and Cellular Biology

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c BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors SNAI1, SNAI2, and TWIST1. We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression. Basic helix-loop-helix (bHLH) type transcription factors play key roles in cell differentiation, proliferation, apoptosis, and metabolism. BHLHE40 (basic helix-loop-helix family member e40 gene) and BHLHE41 are members of the Hairy/E(spl)/HES family. BHLHE40 and BHLHE41 (BHLHE40/41) exhibit more than 90% similarity in the bHLH region and approximately 50% in total. BHLHE40/41 have been shown to function as transcriptional repressors by binding to the class B E-box. BHLHE40/41 interact with TF2B, TBP, or TF2D or recruit a histone deacetylase at the E-box site (1-5). On the other hand, BHLHE40/41 were previously reported to modulate the expression of some genes in an E-box-independent manner. BHLHE40 has been shown to associate with SP1 binding sites in the BIRC5 promoter to activate its transcription (6) and with STAT3 to regulate the transcription of STAT3-dependent target genes (7). BHLHE41 suppressed VEGF transcription by interacting with HIF1A (8). BHLHE40 and BHLHE41 were reported to associate with retinoid X receptor (RXR), MYOD1, or CEBP in order to regulate the transcription of their target genes (9-12).In diverse types of cancer species, such as colon, oral, and liver cancer or brain tumors, BHLHE40 expression levels were found to be higher in tumors than in adjacent normal tissues (13-15). On the other hand, in human endometrial cancer (HEC) and nonsmall-cell lung cancer, no changes in BHLHE40 expression were reported between cancer and normal tissues (16,17). Regarding expression profiles with the development of cancer, studies on oral, lung, liver, and esophageal cancer showed that BHLHE40 expression inversely correlated with the tumor stage or differentiation grade (18-21)...

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“…7E). As reported previously, BHLHE40/41 expression recruited HDAC1 and excluded KAT2B and acetylated histone H3 from the SBS (11,40,41) (Fig. 7E).…”

Section: Clinical Evaluation Of Bhlhe40 and Bhlhe41 Expression In Hecmentioning

confidence: 56%

Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Asanoma

Liu

Yamane

et al. 2015

Molecular and Cellular Biology

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“…They specifically bind to the proximal E2-box to activate PGC-1␣ transcription while a bHLH transcriptional repressor, Bhlhe40, binds to the adjacent E1-box to antagonize this activation. However, this antagonism can be relieved when P/CAF, a key coactivator of MRFs, is supplied in overdose, suggesting the sequestration of P/CAF by Bhlhe40 (16). Bhlhe40 interacts with P/CAF significantly, which reduces the interaction between P/CAF and MyoD.…”

mentioning

confidence: 99%

Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells

Chung

Kao

Villarroya

et al. 2015

Molecular and Cellular Biology

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c PGC-1␣ is a transcriptional coactivator promoting oxidative metabolism in many tissues. Its expression in skeletal muscle (SKM) is induced by hypoxia and reactive oxidative species (ROS) generated during exercise, suggesting that PGC-1␣ might mediate the cross talk between oxidative metabolism and cellular responses to hypoxia and ROS. Here we found that PGC-1␣ directly interacted with Bhlhe40, a basic helix-loop-helix (bHLH) transcriptional repressor induced by hypoxia, and protects SKM from ROS damage, and they cooccupied PGC-1␣-targeted gene promoters/enhancers, which in turn repressed PGC-1␣ transactivational activity. Bhlhe40 repressed PGC-1␣ activity through recruiting histone deacetylases (HDACs) and preventing the relief of PGC-1␣ intramolecular repression caused by its own intrinsic suppressor domain. Knockdown of Bhlhe40 mRNA increased levels of ROS, fatty acid oxidation, mitochondrial DNA, and expression of PGC-1␣ target genes. Similar effects were also observed when the Bhlhe40-mediated repression was rescued by a dominantly active form of the PGC-1␣-interacting domain (PID) from Bhlhe40. We further found that Bhlhe40-mediated repression can be largely relieved by exercise, in which its recruitment to PGC-1␣-targeted cis elements was significantly reduced. These observations suggest that Bhlhe40 is a novel regulator of PGC-1␣ activity repressing oxidative metabolism gene expression and mitochondrion biogenesis in sedentary SKM. Skeletal muscle (SKM) is one of the major metabolic organs, and it has the ability to adapt to various physiological conditions, such as cold, exercise, and sedentary life, by adjusting the balance between glycolytic and oxidative metabolism to meet the energy requirement under these conditions (1). Recent studies suggest that this adaptation relies much on the expression and activity of PGC-1␣, a transcriptional coactivator highly expressed in tissues with high energy metabolism (1, 2). PGC-1␣ enhances the activity of many nuclear receptors (NR), including peroxisome proliferator-activated receptor ␥ (PPAR␥), estrogen receptor (ER), and glucocorticoid receptor (GR), and non-NR transcription factors, such as MEF2, Sox9, FoxO1, and SREBP1 (reviewed in reference 3 and references therein), to promote oxidative metabolism, metabolic thermogenesis adaptation, biogenesis of mitochondria, gluconeogenesis, and fatty acid oxidation in various tissues (4-6). Overexpression of PGC-1␣ can promote metabolic switch from anaerobic glycolysis to oxidative metabolism (7,8). Current studies also show that PGC-1␣ plays critical roles in orchestrating the cellular response to hypoxia (9).In SKM, PGC-1␣ is preferentially expressed in oxidative metabolism-dependent slow-twitch fibers (10), and its overexpression can convert putative fast-twitch fibers into slow-twitch fibers (10). The activation of oxidative and slow-twitch muscle-specific genes by PGC-1␣ is mediated through its coactivation of Mef2 and PPAR binding to the upstream regulatory sites of these target genes (11). PGC-1␣ null mice sho...

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“…These data prove that Ascl2 inhibits myogenesis through repressing the transcriptional activities of MRFs. Our study thus identifies Ascl2 as a novel member of the repressive bHLH factors [which include MyoR, Mist1 (Bhlha15) and Bhlhe40] that compete with MRFs for heterodimerization partners and E-boxes to modulate myogenesis (Hsiao et al, 2009;Lemercier et al, 1998;Lu et al, 1999;Wang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…We next sought to determine how Ascl2 OE inhibits Myog expression. bHLH factors can block myogenesis through competitive binding with transcriptional coactivators (E-proteins) for E-boxes, or by forming inactive heterodimers with MRFs (Hsiao et al, 2009;Lemercier et al, 1998;Lu et al, 1999). To dissect how Ascl2 functions, we first sought to identify Ascl2-associated proteins.…”

Section: Ascl2 Forms Complexes With E-proteinsmentioning

confidence: 99%

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

Wang

Arrington

et al. 2016

Development

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Myogenic regulatory factors (MRFs), including Myf5, MyoD (Myod1) and Myog, are muscle-specific transcription factors that orchestrate myogenesis. Although MRFs are essential for myogenic commitment and differentiation, timely repression of their activity is necessary for the self-renewal and maintenance of muscle stem cells (satellite cells). Here, we define Ascl2 as a novel inhibitor of MRFs. During mouse development, Ascl2 is transiently detected in a subpopulation of Pax7 + MyoD + progenitors (myoblasts) that become Pax7 + MyoD − satellite cells prior to birth, but is not detectable in postnatal satellite cells. Ascl2 knockout in embryonic myoblasts decreases both the number of Pax7 + cells and the proportion of Pax7 + MyoD − cells. Conversely, overexpression of Ascl2 inhibits the proliferation and differentiation of cultured myoblasts and impairs the regeneration of injured muscles. Ascl2 competes with MRFs for binding to E-boxes in the promoters of muscle genes, without activating gene transcription. Ascl2 also forms heterodimers with classical E-proteins to sequester their transcriptional activity on MRF genes. Accordingly, MyoD or Myog expression rescues myogenic differentiation despite Ascl2 overexpression. Ascl2 expression is regulated by Notch signaling, a key governor of satellite cell self-renewal. These data demonstrate that Ascl2 inhibits myogenic differentiation by targeting MRFs and facilitates the generation of postnatal satellite cells.

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P/CAF rescues the Bhlhe40-mediated repression of MyoD transactivation

Cited by 20 publications

References 42 publications

Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells

Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors

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