A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair

González-Suárez, Ignacio; Redwood, Abena B.; Grotsky, David A; Neumann, Martín; Cheng, Emily H.; Stewart, Colin L.; Dusso, Adriana; Gonzalo, Susana

doi:10.1038/emboj.2011.225

Cited by 102 publications

(117 citation statements)

References 53 publications

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“…Prelamin A, the precursor of lamin A, is transiently accumulated during oxidative or replicative stress (Lattanzi et al, 2014; Liu, Drozdov, Shroff, Beltran, & Shanahan, 2013). Moreover, proteins involved in repair of stress‐induced DNA damage are recruited by lamins to damaged sites or inside the nuclear compartment (Gibbs‐Seymour, Markiewicz, Bekker‐Jensen, Mailand, & Hutchison, 2015; Gonzalez‐Suarez et al, 2011; Lattanzi et al, 2014). Consistent with these functions, lamin A/C has been implicated in mechanisms related to physiological (Lattanzi et al, 2014) and pathological aging (Evangelisti, Cenni, & Lattanzi, 2016), above all in progeroid laminopathies (Camozzi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…Cell lines transformed by certain oncogenes, including ras, are known to express high levels of CTSL [12][13][14] . Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] .…”

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confidence: 99%

“…Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] . Although the therapeutic potential of CTSL inhibitors has not been fully characterized in preclinical studies, targeting CTSL activity is considered as a strategy for anticancer therapy 20 .…”

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confidence: 99%

“…However, certain HDACs are essential for normal cells and a therapeutic approach using these pharmacologic inhibitors depends on the tolerance levels of normal cells to the damage caused by the treatment 7,8 . Tumourassociated cysteine protease cathepsin L (CTSL) also has crucial roles at multiple stages of tumour progression and metastasis [9][10][11] . Cell lines transformed by certain oncogenes, including ras, are known to express high levels of CTSL [12][13][14] .…”

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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

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“…1,25D biological actions require 1,25D binding to the cytosolic VD receptor (VDR), which translocates to the nucleus and acts as a transcriptional regulator of the expression of more than 200 genes controlling normal and cancer cell growth, differentiation, DNA repair, apoptosis, angiogenesis, and metastatic potential. [12][13][14] The endometrium is a target of 1,25D/VDR antitumoral actions: in the EEC cell lines, IK, HEC-1A, and RL-95/2, 1,25D treatment induces differentiation, growth arrest, 15 and apoptosis. 16 Importantly, the increased risk for colorectal, 17 breast, 18 and prostate 8,19 cancer in VD-deficient individuals is not the result of defective renal 1,25D synthesis because serum 1,25D, mostly of renal origin, remains normal until serum 25(OH)D levels decrease below 4 ng/ml.…”

mentioning

confidence: 99%

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

Bergadà

Pallarés

Arcidiacono

et al. 2014

Laboratory Investigation

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Vitamin D (VD) deficiency has been suggested as a risk factor for cancer. One recognized mechanism is that the low-serum 25-hydroxyvitamin D (25(OH)D) of VD deficiency reduces intratumoral 25(OH)D conversion to 1a,25-dihydroxyvitamin D (1,25D, the hormonal form of VD), compromising 1,25D-VD receptor (VDR) antitumoral actions. Reduced tumoral VDR and increased CYP24A1, the enzyme that degrades 1,25D and 25(OH)D, further worsen cancer progression. Importantly, in cells expressing CYP27A1 and/or CYP2R1, which convert inert VD into 25(OH)D, low-serum VD may reduce intratumoral 25(OH)D synthesis thereby compromising VDR antitumoral actions because 25(OH)D can activate the VDR directly and enhance 1,25D-VDR action. Therefore, this study examined whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma (EC). Immunohistochemical analysis of tissue microarrays of normal human endometrium (NE; n ¼ 60) and EC (n ¼ 157) showed the expected lower VDR expression in EC (P ¼ 0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P ¼ 0.0002; P ¼ 0.03). Furthermore, in NE and EC, CYP2R1 and CYP27A1 expression correlated directly with nuclear VDR levels, an indicator of ligand-induced VDR activation, and inversely with the proliferation marker Ki67. Accordingly, in the endometrioid carcinoma cell lines IK, RL95/2 and HEC1-A, which express VDR, CYP27A1, and CYP2R1, VD efficaciously reduced cell viability and colony number, with a time course that paralleled actual increases in both intracellular 25(OH)D and nuclear VDR levels. Thus, VD may protect from EC progression in part through increased intratumoral 25(OH)D production by CYP27A1 and CYP2R1 for autocrine/paracrine enhancement of 1,25D-VDR-antiproliferative actions. Endometrial carcinoma (EC) results from neoplastic transformation of normal endometrium (NE) 1 leading to two main clinicopathological variants: endometrioid carcinoma (EEC) and non-endometrioid carcinomas (NEEC). EECs are estrogen-related tumors, frequently well differentiated, and developing mostly in peri-and postmenopausal women. Low grades (1 and 2) tumors are usually confined to the uterus (stage I) while grade 3 EECs are less frequent, with a higher tendency for extrauterine spread. NEEC, either serous or clear cell (CC) carcinomas, occur in older women, are estrogenunrelated tumors, with aggressive behavior and frequent extrauterine spread to the peritoneum or lymph nodes. 2,3 One risk factor for human cancer that can be safely modified is vitamin D (VD) deficiency/insufficiency.

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A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair

Cited by 102 publications

References 53 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

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