Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

Zhang, Huan-Tian; Gui, Tao; Liu, Rixu; Tong, Kui-Leung; Wu, Chong-Jie; Li, Zhenyan; Huang, Xun; Xu, Qiu-Tong; Yang, Jie; Tang, Wang; Sang, Yuan; Liu, Wanting; Liu, Ning; Ross, Ryan D.; He, Qing‐Yu; Zha, Zhengang

doi:10.1038/s41419-021-03416-1

Cited by 19 publications

(9 citation statements)

References 59 publications

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“…Furthermore, the knockdown of YAP1 led to increased expression of the cell cycle inhibitor p21 Cip1/Waf1 ( Figure 2 A). These findings are in accordance with recently reported findings that pharmacological inhibition of YAP1 or YAP1 depletion led to increased expression of p21 and the induction of senescence [ 39 ].…”

Section: Discussionsupporting

confidence: 93%

“…However, as recently reported for rhabdomyosarcoma [ 46 ], it is possible that dasatinib might not be sufficient to phenocopy the effects of RASSF1A, and that the combination of dasatinib with RASSF1A-activating drugs such as DNMTi is needed to suppress YAP1 activity and YAP1-mediated FOXM1 and ERα expression. Notably, it was reported that sequential targeting of YAP1 and p21 led to the elimination of senescent tumor cells [ 39 ]. As senescent cells may contribute to disease recurrence after cancer therapy, the potential clinical application of YAP1 inhibition together with RASSF1A-activating drugs may also require sequential targeting of p21 to shift senescent cells into apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Roßwag

Sleeman

Thaler

2021

Cells

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Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Roßwag

Sleeman

Thaler

2021

Cells

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“…P16 and P53‐P21 are two canonical pathways that control senescence. [ 40,41 ] Our data showed that knockdown of P16 and P21 eliminated Notch‐induced senescence. These findings collectively confirmed the role of the Notch‐Sirt1‐P53‐P21 or Notch‐Sirt1‐P16 axis in regulating LSEC senescence (Figure 7K).…”

Section: Discussionmentioning

confidence: 84%

Shear stress–induced cellular senescence blunts liver regeneration through Notch–sirtuin 1–P21/P16 axis

et al. 2021

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Background and Aims:The mechanisms involved in liver regeneration after partial hepatectomy (pHx) are complicated. Cellular senescence, once linked to aging, plays a pivotal role in wound repair. However, the regulatory effects of cellular senescence on liver regeneration have not been fully elucidated. Approach and Results: Mice subjected to pHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stressinduced endothelial nitric oxide synthase (eNOS) signaling on day 14, resulting in the accumulation of senescent LSECs. Removing macrophages to augment LSEC senescence led to a malfunction of the regenerating liver. A dynamic fluctuation in Notch activity accompanied senescent LSEC accumulation during liver regeneration. Endothelial Notch activation by using Cdh5-CreERT NIC eCA mice triggered LSEC senescence and senescence-associated secretory phenotype, which disrupted liver regeneration. Blocking the Notch by γ-secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch-hairy and enhancer of split 1 signaling inhibited sirtuin 1 (Sirt1) transcription by binding to its promoter region. Activation of Sirt1 by SRT1720 neutralized the up-regulation of P53, P21, and P16 caused by Notch activation and eliminated Notch-driven LSEC senescence. Finally, Sirt1 activator promoted liver regeneration by abrogating LSEC senescence and improving sinusoid remodeling.

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“…Moreover, H&E (three native and three decellularized) and DAPI (three native and three decellularized) images were analyzed quantitatively by counting cell nuclei using ImageJ ITCN plug-in. 44,45 IHC images [collagen IV (three images) and laminin (three images)] were analyzed quantitatively by measuring the percentage of stained area using ImageJ software. 46…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Acellular nipple scaffold development, characterization, and preliminary biocompatibility assessment in a swine model

Oganesyan

Lellouch

Acun

et al. 2022

Plastic &Amp; Reconstructive Surgery

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Background: The standard in nipple reconstruction remains the autologous skin flap. Unfortunately, the results are not satisfying, with up to 75% loss of nipple projection over time. Existing studies investigated the use of primates as a source of implants. The authors hypothesized that the porcine nipple can serve as a perfect shape-supporting implant because of functional similarities to the human nipple. A decellularization protocol was developed to obtain an acellular nipple scaffold (ANS) for nipple reconstruction. Methods: Tissue samples were collected from eight disease-free female Yorkshire pigs (60 to 70 kg) and then decellularized. The decellularization efficiency and extracellular matrix characterization was performed histologically and quantitatively (DNA, total collagen, elastin, and glycosaminoglycan content). In vitro and in vivo biocompatibility was determined by human dermal fibroblast culture and subcutaneous implantation of six ANSs in a single Yorkshire pig (60 to 70 kg), respectively. Inflammation and adverse events were monitored daily based on local clinical signs. Results: The authors showed that all cellular structures and 96% of DNA [321.7 ± 57.6 ng DNA/mg wet tissue versus 11.7 ± 10.9 ng DNA/mg wet tissue, in native and ANS, respectively (P < 0.001)] can be successfully removed. However, this was associated with a decrease in collagen [89.0 ± 11.4 and 58.8 ± 9.6 μg collagen/mg (P < 0.001)] and elastin [14.2 ± 1.6 and 7.9 ± 2.4 μg elastin/mg (P < 0.05)] and an increase in glycosaminoglycan content [5.0 ± 0.7 and 6.0 ± 0.8 ng/mg (P < 0.05)]. ANS can support continuous cell growth in vitro and during preliminary biocompatibility tests in vivo. Conclusion: This is a preliminary report of a novel promising ANS for nipple reconstruction, but more research is needed to validate results. Clinical Relevance Statement: Breast cancer is very common among women. Treatment involves mastectomy, but its consequences affect patient mental well-being, and can lead to depression. Nipple-areola complex reconstruction is critical, and existing methods lead to unsatisfactory outcomes.

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Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1

Cited by 19 publications

References 59 publications

RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Shear stress–induced cellular senescence blunts liver regeneration through Notch–sirtuin 1–P21/P16 axis

Acellular nipple scaffold development, characterization, and preliminary biocompatibility assessment in a swine model

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