Post-translational regulation of proto-oncogene ZBTB7A expression by p53 status in cancer cells: HSP90-dependent stabilization vs. p53-KLHL20-ubiquitin proteasomal degradation.

ZBTB7A overexpressed in many human cancers is a major oncogenic driver. ZBTB7A promotes tumorigenesis by regulating transcription of the genes involved in cell survival and proliferation, apoptosis, invasion, and migration/metastasis. One unresolved issue is the mechanism underlying the aberrant overexpression of ZBTB7A in cancer cells. Interestingly, inhibition of HSP90 decreased ZBTB7A expression in a variety of human cancer cells. ZBTB7A interacts with and is stabilized by HSP90. Inhibition of HSP90 by 17-AAG resulted in p53-dependent proteolysis of ZBTB7A via increased p53 expression and upregulation of the CUL3-dependent E3 ubiquitin ligase, KLHL20. Down-regulation of ZBTB7A resulted in the derepression of a major negative regulator of cell cycle progression, p21/CDKN1A. We discovered a new function of p53 regulating ZBTB7A expression through KLHL20-E3 ligase and proteasomal protein degradation system.

Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2020.

PURPOSE: The current study provides national cancer statistics and their secular trends in Korea, including incidence, mortality, survival, and prevalence in 2020. Materials and Methods: Incidence, survival, and prevalence rates of cancer were calculated using the Korea National Cancer Incidence Database, from 1999 to 2020, with survival follow-up until December 31, 2021. Deaths from cancer were assessed using causes-of-death data obtained from Statistics Korea. RESULTS: The number of new cancer diagnoses in 2020 decreased by 9,218 cases (3.6%) compared to 2019. In 2020, newly diagnosed cancer cases and deaths from cancer were reported as 247,952 (age-standardized rate [ASR], 262.2 per 100,000) and 82,204 (ASR, 69.9 per 100,000), respectively. The overall cancer incidence rates increased by 3.3% annually from 1999 to 2012, and decreased by 5.0% annually from 2012 to 2015, thereafter, followed by nonsignificant changes. Cancer mortality rates have been decreasing since 2002, with more rapid decline in recent years. The 5-year relative survival between 2016 and 2020 was 71.5%, which contributed to prevalent cases reaching over 2.2 million in 2020. CONCLUSION: In 2020, the number of newly diagnosed cancer patients decreased due to the coronavirus disease 2019 pandemic, but the overall trend is on the rise. Cancer survival rates have improved over the past decades. As the number of cancer survivors increases, a comprehensive cancer control strategy should be implemented in line with the changing aspects of cancer statistics. The long-term impact of the coronavirus disease 2019 pandemic on cancer statistics needs to be investigated in the future.

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

KRAS Mutants Upregulate Integrin ß4 to Promote Invasion and Metastasis in Colorectal Cancer.

KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6ß4 through ERK/MEK signaling. Knocking-out integrin ß4 (ITGB4) specifically depleted the expression of integrin α6ß4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6ß4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate. IMPLICATIONS: Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.

An immunocompetent rectal cancer model to study radiation therapy.

We describe a mouse model of rectal cancer (RC) involving rapid tumor organoid engraftment via orthotopic transplantation in an immunocompetent setting. This approach uses simple mechanical disruption to allow engraftment, avoiding the use of dextran sulfate sodium. The resulting RC tumors invaded from the mucosal surface and metastasized to distant organs. Histologically, the tumors closely resemble human RC and mirror remodeling of the tumor microenvironment in response to radiation. This murine RC model thus recapitulates key aspects of human RC pathogenesis and presents an accessible approach for more physiologically accurate, preclinical efficacy studies.

An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage.

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.

Proto-oncoprotein Zbtb7c and SIRT1 repression: implications in high-fat diet-induced and age-dependent obesity.

Zbtb7c is a proto-oncoprotein that controls the cell cycle and glucose, glutamate, and lipid metabolism. Zbtb7c expression is increased in the liver and white adipose tissues of aging or high-fat diet-fed mice. Knockout or knockdown of Zbtb7c gene expression inhibits the adipocyte differentiation of 3T3-L1 cells and decreases adipose tissue mass in aging mice. We found that Zbtb7c was a potent transcriptional repressor of SIRT1 and that SIRT1 was derepressed in various tissues of Zbtb7c-KO mice. Mechanistically, Zbtb7c interacted with p53 and bound to the proximal promoter p53RE1 and p53RE2 to repress the SIRT1 gene, in which p53RE2 was particularly critical. Zbtb7c induced p53 to interact with the corepressor mSin3A-HADC1 complex at p53RE. By repressing the SIRT1 gene, Zbtb7c increased the acetylation of Pgc-1α and Pparγ, which resulted in repression or activation of Pgc-1α or Pparγ target genes involved in lipid metabolism. Our study provides a molecular target that can overexpress SIRT1 protein in the liver, pancreas, and adipose tissues, which can be beneficial in the treatment of diabetes, obesity, longevity, etc.

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

Pharmacologic Inhibition of HIF-1α Attenuates Radiation-Induced Pulmonary Fibrosis in a Preclinical Image Guided Radiation Therapy.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF. METHODS AND MATERIALS: An inducible Cre-lox-mediated endothelial Hif1a deletion mouse line was used to evaluate the potential of HIF-1α inhibition to suppress RIPF. To evaluate the effects of a pharmacologic HIF-1α inhibitor on RIPF after image guided radiation therapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-RasG12D; and p53 flox/flox mice to facilitate tracking of tumor cells expressing tdTomato. RESULTS: We found that vascular endothelial-specific HIF-1α deletion shortly before radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1α before irradiation did not. Moreover, we revealed that postirradiation treatment with the novel HIF-1α inhibitor, 2-methoxyestradiol (2-ME) could efficiently inhibit RIPF and EndMT. In addition, IGRT using primary mouse models of non-small cell lung cancer showed that combined treatment of 2-ME with ablative high-dose radiation therapy efficiently inhibited RIPF and the growth of both multifocal and single tumors, concomitantly reducing radiation-induced EndMT of normal as well as tumor regions. CONCLUSION: These results suggest that a negative regulator of HIF-1α-mediated EndMT, such as 2-ME, may serve as a promising inhibitor of RIPF in radiation therapy.

Cell fate decisions by c-Myc depend on ZBTB5 and p53.

The oncoprotein, c-Myc, not only promotes cell proliferation, but can also induce or sensitize cells to apoptosis. However, how c-Myc decides cell fate and which c-Myc downstream target genes are involved remain unknown. Previously, we showed that ZBTB5 (zinc finger and BTB domain-containing 5) is a proto-oncogene that stimulates cell proliferation. ZBTB5 represses p21/CDKN1A by competing with p53 and recruiting corepressor histone deacetylase complexes. Herein, we found that c-Myc directly activates the transcription of ZBTB5. In the absence of p53, ZBTB5 is acetylated at K597 by interacting with p300, and activates transcription of NOXA, which induces apoptosis. In contrast, in the presence of p53, ZBTB5 interacts with p53 and acetylation at ZBTB5 K597 is blocked. ZBTB5 without K597 acetylation interacts with mSin3A/HDAC1 to repress p21/CDKN1A transcription and promote cell proliferation. Cell fate decisions by c-Myc depend on ZBTB5, p53 and p300, and acetylation of ZBTB5 K597.

KLHL4, a novel p53 target gene, inhibits cell proliferation by activating p21WAF/CDKN1A.

KLHL4 is a member of the KLHL protein family, many of whom bind the Cul3 E3 ligase, and mediate the ubiquitination of interacting proteins. The KLHL4 gene, localized on the X chromosome, associates with a disorder known as X-linked cleft palate (CPX). However, the biological functions of KLHL4 are largely unknown. In this study, microarray analysis of HEK293A embryonic kidney cells, expressing ectopic p53, showed a 3-fold increase of KLHL4 mRNA. Moreover, both KLHL4 mRNA and protein expression were elevated by p53 or DNA damage, suggesting that KLHL4 might be a p53 target gene. We also found that KLHL4 activates transcription of p21WAF/CDKN1A, a p53 target gene encoding a major negative regulator of the cell-cycle. KLHL4 interacted with p53 to increase its binding to p53 response element of the p21WAF/CDKN1A gene, resulting in transcriptional upregulation. Furthermore, we observed that KLHL4 can interact with the Cul3 ubiquitin ligase, to possibly play a role in ubiquitin-mediated proteasomal degradation, and Klhl4 knocked-out MEF mouse embryonic fibroblasts proliferated faster than WT MEF cells. These results suggest that KLHL4 upregulation by p53 may inhibit cell proliferation, by activating p21WAF/CDKN1A.

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage.

Endothelial-to-mesenchymal transition (EndMT) involves the phenotypic conversion of endothelial-to-mesenchymal cells, and was first discovered in association with embryonic heart development. EndMT can regulate various processes, such as tissue fibrosis and cancer. Recent findings have shown that EndMT is related to resistance to cancer therapy, such as chemotherapy, antiangiogenic therapy, and radiation therapy. Based on the known effects of EndMT on the cardiac toxicity of anticancer therapy and tissue damage of radiation therapy, we propose that EndMT can be targeted as a strategy for overcoming tumor resistance while reducing complications, such as tissue damage. In this review, we discuss EndMT and its roles in damaging cardiac and lung tissues, as well as EndMT-related effects on tumor vasculature and resistance in anticancer therapy. Modulating EndMT in radioresistant tumors and radiation-induced tissue fibrosis can especially increase the efficacy of radiation therapy. In addition, we review the role of hypoxia and reactive oxygen species as the main stimulating factors of tissue damage due to vascular damage and EndMT. We consider drugs that may be clinically useful for regulating EndMT in various diseases. Finally, we argue the importance of EndMT as a therapeutic target in anticancer therapy for reducing tissue damage.

A rectal cancer organoid platform to study individual responses to chemoradiation.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

Temporal and differential regulation of KAISO-controlled transcription by phosphorylated and acetylated p53 highlights a crucial regulatory role of apoptosis.

Transcriptional regulator KAISO plays a critical role in cell cycle arrest and apoptosis through modulation of p53 acetylation by histone acetyltransferase p300. KAISO potently stimulates apoptosis in cells expressing WT p53, but not in p53-mutant or p53-null cells. Here, we investigated how KAISO transcription is regulated by p53, finding four potential p53-binding sites (p53-responsive DNA elements; p53REs) located in a distal 5'-upstream regulatory element, intron 1, exon 2 coding sequence, and a 3'-UTR region. Transient transcription assays of pG5-p53RE-Luc constructs with various p53REs revealed that p53 activates KAISO (ZBTB33) transcription by acting on p53RE1 (-4326 to -4227) of the 5'-upstream region and on p53RE3 (+2929 to +2959) of the exon 2 coding region during early DNA damage responses (DDRs). ChIP and oligonucleotide pulldown assays further disclosed that p53 binds to the p53RE1 and p53RE3 sites. Moreover, ataxia telangiectasia mutated (ATM) or ATM-Rad3-related (ATR) kinase-mediated p53 phosphorylation at Ser-15 or Ser-37 residues activated KAISO transcription by binding its p53RE1 or p53RE3 sites during early DDR. p53RE1 uniquely contained three p53-binding half-sites, a structural feature important for transcriptional activation by phosphorylated p53 Ser-15·Ser-37. During the later DDR phase, a KAISO-mediated acetylated p53 form (represented by a p53QRQ acetyl-mimic) robustly activated transcription by acting on p53RE1 in which this structural feature is not significant, but it provided sufficient KAISO levels to confer a p53 "apoptotic code." These results suggest that the critical apoptosis regulator KAISO is a p53 target gene that is differently regulated by phosphorylated p53 or acetylated p53, depending on DDR stage.

Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A.

Overexpressed Solute Carrier Family 16 Member 3 (SLC16A3, also called MCT4) plays a critical role in hypoxic cancer cell growth and proliferation, by expelling glycolysis-derived lactate across the plasma membrane. However, how SLC16A3 expression is regulated, under hypoxic conditions, is poorly understood. FBI-1, encoded by ZBTB7A, is a proto-oncoprotein. Interestingly, under hypoxic conditions, expression of SLC16A3, and hypoxia-inducible factor-1 (HIF-1), increased gradually, while FBI-1 expression decreased, suggesting a negative correlation between SLC16A3/HIF-1 and FBI-1 expression. Consequently, we hypothesized that FBI-1 might regulate SLC16A3 and/or HIF-1 expression. Transient transfection and transcription assays of SLC16A3 promoter reporter fusion constructs, oligonucleotide-pulldowns, and ChIP assays, showed that HIF-1α activates SLC16A3 by binding to a hypoxia-response element (HRE), while ectopic FBI-1 potently repressed SLC16A3, by binding to both FBI-1-response elements (FREs) and HREs, during hypoxia. Further evidence for this model was downregulation of ZBTB7A, correlated with SLC16A3 upregulation, in hypoxic colon cancer cells. We also investigated how FBI-1 expression is downregulated during hypoxia. The 5'-upstream regulatory region of ZBTB7A contains two NF-κB-binding sites and two HREs. Interestingly, hypoxia activated NF-κB (RelA/p65) and also increased its nuclear translocation. NF-κB repressed ZBTB7A by binding NF-κB-binding elements, and downregulated the repressor FBI-1, thereby increasing SLC16A3 transcription. While transcriptional repression of SLC16A3 by FBI-1 inhibited lactate efflux, repression of ZBTB7A and activation of lactate efflux by NF-κB, increased colon cancer cell growth and proliferation.

Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6+ cancer cell and macrophage polarization.

It remains controversial whether targeting tumour vasculature can improve radiotherapeutic efficacy. We report that radiation-induced endothelial-to-mesenchymal transition (EndMT) leads to tumour vasculature with abnormal SMA+NG2+ pericyte recruitment during tumour regrowth after radiotherapy. Trp53 (but not Tgfbr2) deletion in endothelial cells (ECs) inhibited radiation-induced EndMT, reducing tumour regrowth and metastases with a high CD44v6+ cancer-stem-cell (CSC) content after radiotherapy. Osteopontin, an EndMT-related angiocrine factor suppressed by EC-Trp53 deletion, stimulated proliferation in dormant CD44v6+ cells in severely hypoxic regions after radiation. Radiation-induced EndMT significantly regulated tumour-associated macrophage (TAM) polarization. CXCR4 upregulation in radioresistant tumour ECs was highly associated with SDF-1+ TAM recruitment and M2 polarization of TAMs, which was suppressed by Trp53 deletion. These EndMT-related phenomena were also observed in irradiated human lung cancer tissues. Our findings suggest that targeting tumour EndMT might enhance radiotherapy efficacy by inhibiting the re-activation of dormant hypoxic CSCs and promoting anti-tumour immune responses.

ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding.

Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.

Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response.

Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-ß signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.

Effects of NOX1 on fibroblastic changes of endothelial cells in radiation­induced pulmonary fibrosis.

Lung fibrosis is a major complication in radiation­induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre­treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, ­2 or ­4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1­specific inhibitor suppressed radiation­induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation­induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs.

HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis.

The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFß or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.